FOOD AND DRUG ADMINISTRATION
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OBSTETRICS AND GYNECOLOGY DEVICES PANEL
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SEVENTY-FIRST MEETING
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OPEN SESSION
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Tuesday, March 28, 2006
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The Panel met at 9:00 a.m. in the Ballroom of the
Gaithersburg Hilton, Gaithersburg, Maryland, Kenneth Noller, M.D., Chair,
presiding.
PRESENT:
KENNETH NOLLER,
M.D. Chair
PAULA HILLARD,
M.D. Voting Member
HUGH MILLER, M.D. Voting
Member
JONATHAN WEEKS, M.D. Voting
Member
MARCELLE
HOWARD SHARP, M.D. Voting
Member
JOSEPH SANFILIPPO,
M.D. Voting Member
DIANA ROMERO,
Ph.D. Consumer Representative
ELISABETH GEORGE Industry
Representative
GERALD SHIRK, M.D. Consultant
SCOTT EMERSON, M.D.,
Ph.D. Consultant
NASSER CHEGINI,
Ph.D. Consultant
NANCY SHARTS-HOPKO,
R.N., Ph.D. Consultant
RUSSELL SNYDER,
M.D. Consultant
MICHAEL T. BAILEY,
Ph.D. Executive Secretary
NANCY C. BROGDON Division Director
The Chairman called
the open session to order at 9:02 a.m. and had the members introduce
themselves. Dr. Bailey reviewed the
remaining tentative Panel meeting dates for 2006. He read the conflict of interest statement
into the record. No COI waivers have
been issued for this meeting. Members
were asked to recuse themselves if an issue arises in which they have a
financial interest.
Colin
Pollard, Chief of the Obstetrics and Gynecology Devices Branch, started by
announcing the FDA’s Centennial year.
There have been significant developments lately in condom labeling, the
STAN fetal heart monitor, the OxiFirst fetal pulse oximeter, and the LUMA
cervical imaging system. Last year, the
Center issued a Notice of Proposed Rulemaking asking for more specific
information on condom labeling about protection from STDs, highlighting that
they work better against STDs like HIV/AIDS than those like herbes or HPV. The 90-day comment period ended last month.
In June, the Panel recommended approval of the STAN fetal heart
monitor, and the PMA was approved in November.
It is approved as an adjunct to conventional monitoring to determine
whether intervention is warranted when there is increased risk of developing
metabolic acidosis. It is intended to be
used for patients with planned vaginal delivery, greater than 36 weeks completed
gestation, singleton fetus, vertex presentation, and ruptured membranes. The Panel recommended post-approval studies,
but the FDA did not make that a condition of approval. However, the device will be tracked through
the MDR Adverse Event Reporting System and the MedSen Network.
The PMA for the OxiFirst fetal oxygen saturation monitoring
system was approved in 2000, and two others were approved for manufacturers
licensing the same technology. The PMAs
required studies. The manufacturer
completed the first study, and the NIH did a large study called the FOX trial,
which failed to show an impact of the technology on Caesarian delivery rates
for both the overall population as well as the indicated population of labors
with a nonreassuring fetal heart rate.
The manufacturer has voluntarily stopped marketing the monitor, although
it will continue to provide technical support to customers still using the
monitor with remaining disposable centers at hand. The firm will also continue to fulfill other
PMA requirements.
The LUMA Surgical Imaging System is indicated as an adjunct to
colposcopy for the detection of cervical cancer precursors. Last May the Panel recommended that this PMA
be disapproved, but the FDA approved the device. Analysis of the study results after the
meeting led the Center to view the two endpoints as a ratio rather than
independently. While LUMA results in
four false positives for every true positive that colposcopy missed, that was
considered acceptable due to the low risk associated with biopsies. Further analysis by MediSpectra showed that a
high LUMA score has a direct relationship to the probability of a biopsy being
positive. The decision was based on post
hoc analyses not pre-specified in the study design and not available to the
Panel when they made their decision.
The PMA requires that the labeling clearly and unequivocally,
define use of the technology as a thorough colposcopy first with commitment to
biopsy sites, followed by evaluation of the LUMA image and identification of
any additional biopsy sites, without subtracting any committed to by
colposcopy. MediSpectra has implemented
new software that facilitates this device use sequence. The labeling also clearly indicates that use of
the LUMA technology will inevitably lead to additional biopsies, and that it is
unknown whether additional colposcopically-directed biopsies would yield
comparable results. Training was
implemented to underscore these aspects of the device use. One condition of approval is that the sponsor
conduct a post-market study to answer some of the remaining questions about the
technology.
Colin Pollard presented
on symptomatic uterine fibroids.
Symptomatic uterine fibroids lead to thousands of hysterectomies every
year. A variety of technologies are
emerging to treat them. The variety of
size, location, and number of fibroids, along with the symptoms patients
manifest makes the matter of determining what endpoints to use for a clinical
trial tricky. Randomization is difficult
because the patients must be offered something they would want done to
them. Finally, some of the devices being
made require a high degree of surgical skill.
The Panel’s task was to look at symptomatic uterine fibroids, new
treatment technologies, and clinical trial design.
In the past, the FDA has used many different endpoints:
bleeding scores, quality of life instruments, contrast-enhanced MRI imaging,
and whether or not the patient returned to surgery. In one ultrasound trial, firms used a nonrandomized
control group with hysterectomies, though the Panel questioned the value of a
nonrandomized arm.
The Panel is charged to consider the papers provided, listen to
the speakers, and discuss what kind of studies are needed to answer the
important questions, using the discussion questions as a framework. There is no application before the Panel, so
there will be no vote.
The Chairman started
the open public hearing, reminding the speakers to disclose any financial
relationships at the beginning of the statement.
Dr. Nadir Alikacem of
InSightec North America presented on ExAblate 2000, an MR-guided focused
ultrasound device. The device has
already approved. It offers an
outpatient procedure as an alternative to surgery for certain patients. The procedure offers a next-day return to
normal life, management of symptom relief, and realtime visualization and
control.
MR-guided focused ultrasound uses high intensity focused
ultrasound to ablate tissue such as a fibroid, using heat, and MR imaging to monitor
the treatment with three-dimensional anatomic information. The MR also visualizes the ultrasound beam,
and MR. thermometry can be achieved during the treatment itself. When the treatment is finished, the MR can
give a realtime outcome.
In clinical trials, a study endpoint must take into account
management of patient symptoms as well as management of patient lifestyle. The study must also take into account the
lifetime of the device as well as its continuous R&D innovation.
Dr. Fred Burbank of Vascular Control Systems presented on the
Flotstat System, a device that allows obstetricians and gynecologists to
identify and control the uterine arteries transvaginally, without surgery. The system has three parts, each of which has
passed a 510(k): a transceiver ultrasound box that does not generate energy or
heat; a guiding tenaculum, and a vascular clamp. The tenaculum attaches to the cervix to guide
the vascular clamp to the area of the uterine arteries in the three o'clock and
nine o'clock position. When advanced
along the guiding tenaculum, the clamp can fold the urinary arteries
posterially and superially and, when closed, can occlude the urinary arteries
for a brief period of time.
Women with fibroids tend to have menorrhagia as well as bulk
symptoms measured by quality of life instruments or uterine imaging. A woman seeking Flotstat therapy seeks to
continue to have menstrual cycles, have reduced menstrual blood flow, and have
improvement in quality of life related to the treatment. Therefore, the metrics used are the Ruta
scale and quality of life metrics
The pilot shows that of women treated with the system, 100
percent returned to continued menstrual cycles.
Of those who had a menstrual cycle, 81 percent had a 50 percent or
greater reduction in their menorrhagia score on the Ruta scale. Of that 81 percent, 80 percent experienced
improvement in quality of life on the SF-12 questionnaire.
John Greenbaum, an independent consultant for Biocompatibles,
UK Ltd. And their distributor, Terumo Interventional Systems, spoke on the
embolization agents GelSpheres, BeadBlock, LC Bead, and Precision Beads. These microspheres are 100 to 1000 microns in
size and, in uterine fibroid embolization, are put into the uterine
artery. There is thrombus formation, and
the fibroid infarcts or shrinks down.
GelSpheres and BeadBlock have been cleared for embolization of
hypervascular tumors and arteriovenous malformations. They were originally cleared as Class III
devices before FDA put out the special controls guidance on embolization
devices that reclassified the devices as Class II special controls. The company is concerned because the guidance
document states that the health risks of vascular embolization are the same as
the risks of neurovascular embolization.
As a result, the companies are trying to obtain a 510 (k) approval when
they have already obtained a five percent clearance based solely on preclinical
and laboratory data with no clinical study for much higher risk procedures in
neurological embolization.
Dr. Phyllis J. Gee of
the North Texas Uterine Fibroid Institute, who performs MR guided focused
ultrasound and is a principle investigator for InSightec, presented on the
device. It operates like a magnifying
glass to focus the ultrasound only on the specific point to be destroyed or
ablated. The MRI is used in planning and
for imaging and temperature feedback during the treatment.
Patients want procedures that give good symptom relief, are
minimally invasive, have a low incidence of adverse events, do not require
follow-up, allow a rapid recovery, and are less disruptive to their way of
life. Physicians want low risk,
efficacy, prompt improvement of symptoms, real time feedback, minimal
invasiveness, and for the procedure to not preclude other options in the
future. The trials for ExAblate 2000
followed symptoms and quality of life.
Dr. Jessica Grossman is the CEO of Gynesonics,
a company developing a minimally invasive device for the treatment of fibroid
tumors, a single needle RF electrode probe that is inserted transvaginally,
transcervically, or laparoscopically.
Using ultrasound for imaging and guidance, the device would deliver
radiofrequency (RF) energy to the target area to ablate or desiccate the tissue. A thermocouple at the tip of the electrode
does realtime temperature monitoring.
There are predicate devices already cleared, such as
VersaPoint, which was cleared by 510(k) and required no clinical trial
data. Substantial equivalence can be
demonstrated by bench testing, and because the mechanism of action is
well-known and of extremely low risk to the patient, clinical trials should not
be required for all technologies for treatment of fibroids. Least burdensome principles apply.
Dr. Sew-Wah Tay
presented for American Medical Systems.
AMS is in the early stages of exploring different approaches to fibroid
treatment. The objective is to develop a
tool to aid gynecologists in treating fibroids via minimally invasive surgery
and allow patients to retain their uteruses.
The device will be used as a first line of treatment with hysterectomy
as a backup if it doesn’t work. They are
looking into using cryomolysis.
In considering what the study should look like, they have
considered what the endpoints should be.
Because most fibroids are benign, the study endpoints should be symptom
relief and quality of life improvement.
The best option seems to be the Symptom Severity Score (SSS), which is a
subscore for the UFS Quality of Life.
AMS will consider an improvement of more than 10 points six months after
treatment to be a success.
Developing a control population will be difficult. Hysterectomy is the most common treatment,
but that is invasive and SSS will not apply to patients without a uterus. UAEs could be used, but they are not the
standard of care and they are not done by gynecologists. Sham surgery is not an option because it is unethical. The most feasible study will be a single arm
study using the patient as her own control and using the UFS Quality of Life
vehicle.
Dr. Bryan Cowan of the
He is developing a research protocol to assess safety and
efficacy of percutaneously laparoscopically assisted cryomyolysis (PLC) for
treatment of symptomatic uterine fibroids.
The protocol has two endpoints: efficacy and safety. The efficacy endpoint is Symptom Severity
Subscale of the Uterine Fibroid Symptom and Health Related Quality of Life
Questionnaire, the SSF-UFS QoL published in 2002. The safety endpoint is treatment-related
major operative and post-operative complications.
There will be two control groups. For efficacy, the patient is her own control
because there is no other appropriate control group. For safety the study population will be
compared to the laparoscopic supercervical hysterectomy population, since the
patients report with the same symptoms and both procedures use laparoscopy. This control cannot be randomized.
The inclusion demographics of this study would be premenopausal
women who have completed childbearing.
Three types of fibroids would be treated: intramural, sub-serosal, and
sub-mucosal type II. The patient would
have to be symptomatic but have a QoL score greater than 40 points.
For a patient, success would be defined as a ten-point
improvement of SSS-UFS-QOL at six months.
The study will be a success if 50 percent of the patients demonstrate
success.
Dr. Anthony C. Venbrux
of
The procedure is not for every woman with fibroids. About 1 in 50,000 women have a contrast
reaction. Non-target embolization is a
danger, and there is a 4 percent risk of ovarian failure and premature
menopause in 35-year-old women. In
45-year-old women, the risk jumps to 14 percent. As the doctor began to describe how to
perform the technique, he ran out of time.
Dr. Seth Stabinsky is a
shareholder in
Mr. Pollard responded
to the open session, thanking the speakers for their input. To the comments about embolic products and
the related guidance document, he clarified that the document accompanied a
reclassification of the general category of certain kinds of embolic products
from Class 3 to Class 2, and uterine artery embolization was included. That was done to recognize that the FDA had
cleared two 510(k)s for embolic particles, but the policy on treating fibroids
and the clinical trials had not changed.
The FDA may later develop a guidance document specifically for UAE. No clinical data was needed for neurologic
and other peripheral vascular applications because the risk profile is
different.
The Chairman opened the
Panel Discussion.
Question 1: The
primary symptom of problematic fibroids is bleeding. Other symptoms include
pain, urinary problems, infertility, bulk symptoms, etc. Please discuss what
you believe to be the most appropriate parameter to use in the evaluation of
device effectiveness (e.g., bleeding score self-report, measurement of fibroid
size (or perfusion) after surgery, quality-of-life instruments, other).
The Chairman said that the Panel
recognizes that this is a difficult area.
Most women with fibroids do not have symptoms. Those who have symptoms don’t have the same
symptoms. He disagreed with the
statement that the primary symptom of problematic fibroids is bleeding, since
there are so many different symptoms.
Dr. Shirk compared the matter to establishing the criteria for
endometrial ablation. The technique was
intended to treat abnormal uterine bleeding in women. Those women were not going to reproduce. Bleeding was the only issue, so it was graded
with a PBLAC score, a scoring system that uses specialized tampons and
pads. The patient had to have 150 ml of
blood loss to qualify the study, and an endpoint of 75 ml of blood loss was
considered a success. With fibroids,
there are more issues. There are other
symptoms. Some patients have other
uterine pathology. Many of the patients
are approaching menopause. Fibroids can
be cured with a hysterectomy. Patients
looking for other treatments are trying to avoid hysterectomies, so the issue
is one of quality of life rather than achieving an objective goal. If an objective goal is needed, bleeding
scores or fibroid size reduction could be used.
Dr. Sanfilippo suggested looking at the literature. A study published in Fertility and Sterlility
comparing uterine artery embolization and laparoscopic myomectomy used quality
of life as the endpoint. Dr. Snyder said
that the important endpoint is how many patients eventually need a
hysterectomy. Dr. Sharp pointed out that
there are objective and subjective outcomes.
The problem with subjective outcomes is that patients in studies often
want to please the investigator. It
would be worthwhile to have objective data, such as how the devices affect the
tumor.
Dr. Cedars said that the primary indication is the symptoms,
and that has to be the endpoint, since there is no medical reason to remove a
fibroid. The Chairman pointed out that
the placebo effect would affect quality of life scores. Dr. Cedars agreed but added that the placebo
effect wears off and won’t affect results later on.
Dr. Emerson said that if fibroids were the cause of the
symptoms, then there should be an objective measure of fibroids. He also added that repeat treatments are not
bad if the treatment is minimally invasive and didn’t cause adverse
events. Addressing placebo affect, he
said there are three things called by that name: one is the true placebo effect, second is the
natural progression of the disease having nothing to do with the treatment, the
third is the fact that a woman who has symptoms that get better and worse is
likely to go to the doctor when the symptoms are at their worst. This is called regression to the mean, and it
is part of why a study cannot use a patient as her own control because what you
are actually measuring is change in the patient. Perhaps different symptoms would require
different trials.
Dr.
Chegini said that patients being treated for infertility have to be treated
differently, since hysterectomy is not an option. Because African Americans are having more
symptomatic fibroids than Caucasians, the studies populations should be
representative. Another issue is the
necrotic cells left in a patient can cause problems, and the studies should
look at that. Dr. Shirk agreed that the
safety issue was a concern; with uterine embolization, fibroids can slough out
or get infected. This is important when
discussing necrosing technologies. There
is no data on these technologies as far as reproduction and incidence of
uterine rupture. If women are using the
technologies to maintain reproductive status, this will be important to
know. Dr. Sanfilippo said that the
inclusion criteria should include the question of whether or not the patient is
interested in future fertility and treat the women as two separate populations,
then the study should also monitor inadvertent conceptions in those who were
not interested in fertility. Dr. Hillard
said that background reproductive function and menstrual function associated
with age is important to consider as well.
Dr. Sanfilippo said that there must also be criteria for rapid
growth of mass that turns out to be malignant.
Ms. George commented that all of this stratification of data
and analysis will delay getting products out.
It might be better to restrict the usage indications, use very specific
populations, and get the products out.
Indications could be expanded later, as more is learned either through
post-market studies or in separate submissions.
Dr. Shirk emphasized that no matter what the FDA recommends, nothing
prevents a physician from using devices off label.
Dr. Chengini emphasized the substantial biological difference,
not only between normal tissue and tumors but also between African American and
Caucasian. With the differences between
patients, there have to be hard objective numbers. Otherwise, a statistical analysis has little
meaning. He also pointed out that some
of the smaller fibroids are problematic, but the technology cannot detect or
treat those. This has to be considered
in the criteria of a study.
The Chairman proposed using a bleeding tool for bleeding, a
quality of life tool, and an objective measure of mass. That would give a mixture of objective and
subjective scores. Dr. Snyder agreed,
but he pointed out that size doesn’t correlate with change in symptoms, and
reperfusion probably doesn’t either. Dr.
Sharts-Hopko said that compliance may be difficult with self-assessment
bleeding tools unless the process is simplified. Dr. Romero argued that when multiple
endpoints, some endpoints won’t apply to some patients. Instead, he would prefer to see a study
design that matches the endpoints to the presentation by the patient. He also said that many racial disparities are
due to psychosocial issues and don’t really apply to a scientific study. Dr. Snyder pointed out that as study groups
are divided into subgroups, the groups will have to get larger to facilitate
that.
Dr. Shirk asked, when setting a bleeding endpoint, whether it
is to look for a percentage of reduction or to set a ceiling on the amount of
bleeding.
Dr. Miller said that the invasiveness of the procedure is a
quality of life issue and should be considered.
Dr. Emerson wanted the study to look at the safety concerns of
leaving necrotic tissue in the body and the risk of embolizing the wrong blood
vessels. He also raised the distinction
between efficacy (removing fibroids) and effectiveness (treating symptoms).
Question 2: Based on your response to the previous
question, please comment on any specific inclusion and/or exclusion criteria
that should be made part of the eligibility criteria for subject enrollment,
including minimum or appropriate baseline scores, measurements or symptom
level.
The Chairman said that the women should be
between 18 and 40. Dr. Cedars said that patients who want future fertility and
those who do not are separate groups that should be studied separately. However, there are more women who do not want
to preserve fertility, so the industry may not make a device for the smaller
group. Also, in many perimenopausal
women the fibroids are unrelated to the bleeding, so they should be screened
out. Dr. Hillard agreed that failure of
other therapies, including hormonal therapy, should be a criterion. Dr. Emerson asked whether that exclusion
would be to eliminate people for whom the therapy would not work or for whom it
would not be safe. Safety is the larger
issue, since irrelevant data points can be dealt with statistically. Dr. Snyder said that it is important to treat
what is causing the problem. Otherwise,
there is the safety issue of overlooking another reason for the bleeding, such
as endometrial or cervical cancer.
Dr. Weeks said that if not seeking future fertility is an
inclusion criterion, then hysterectomy can be used as a control. He suggested a subgroup of women who do want
future childbearing and have symptoms, but not symptoms severe enough to seek a
hysterectomy or myomectomy.
Dr. Romero said that if fibroids were not the cause of the
symptoms, the patient should not be included in a study to prevent
fibroids. Dr. Shirk pointed out that the
location of the fibroid affects its symptoms.
Submucosal fibroids are more likely to cause bleeding, but they are also
more likely to slough off after an embolization.
Mr. Pollard commented that there was a lack of women desiring
future fertility coming in the studies.
He asked the Panel whether those women should be included and whether
they should be tracked for pregnancy.
Dr. Snyder said that unless future trials looked at pregnancy, there
will be no way to counsel patients who conceive in the future. Dr. Cedars said that those who want to retain
fertility and those who do not are two separate populations with different
views of success. Perhaps a future study
in patients who wanted to maintain fertility could use myomectomy as a
control. Dr. Miller said that the size
of the population and the risk of liability is going to be a disincentive to
companies’ including women who want to remain reproductively active. Dr. Weeks said that the way to look at future
fertility is to look at patients who have had pregnancy losses due to
fibroids. Dr. Shirk said that rupture is
an issue in pregnancy, but the main question is whether or not a pregnancy can
be achieved.
The Chairman opened the floor for input from the audience. Dr. Keith Isaacson, who was not a consultant
in today’s discussion, commented on objective measurements. Fibroid size is not an effective measurement
because embolization data shows that fibroids can reduce in volume by 15 or 40
percent and still have the same effect on symptomology. In fact, smaller fibroids can cause more
bleeding than larger ones. Because there
is no hormonal treatment for fibroids, failure of hormonal therapy can’t be a
criterion.
Dr. Greenbaum of Biocompatibles said that patients go to the
doctor because they want symptoms treated.
The patient is not interested in the fibroids. The endpoints should reflect the symptoms for
which the patient sought treatment. He
urged that time be put into comprehensive bench and laboratory preclinical
testing. UFS QoL is a validated
fibroid-specific tool for bleeding.
PBLAC use can harm compliance.
Dr. Seth Stabinsky said that no company would want to work with
the pregnancy issue, even if it is important to know about pregnancy. NIH should address that issue and do studies
on that.
Dr. Tay from AMS said that the UFS QoL is a composite fibroid
symptom questionarre that covers most of the issues the Panel has discussed.
Dr. Alikacem from Insightec pointed out that there is a
difference between fertility and making pregnancy safe. The Chairman moved to question 4, feeling
that question 3 had been addressed in the previous discussion.
Question 4: Selection
of an appropriate control arm for surgical procedures can be challenging. In
the past, the Panel has criticized a non-randomized control group of
hysterectomy patients. For some procedures, a sham control is not possible.
Discuss other possible control options, e.g., myomectomy vs. no control (i.e.,
patient serving as her own control). What is the role of randomization?
Dr. Sharp said that uterine artery embolization would be a
reasonable control. It could be
randomized, but not blind. A
hysterectomy is not a reasonable comparator to a minimally invasive
technique. Dr. Cedars said that the
problem with uterine artery embolization is that it has not been used in people
who want to preserve fertility and is not the gold standard. Hysterectomies and myomectomies are;
myomectomies should be the control. Dr.
Shirk said that women looking into necrosing procedures do so to avoid surgery,
so a surgical arm to the study would not be acceptable and uterine artery
embolization is a better choice.
The Chairman raised the issue of having no control. Dr. Emerson said that this approach is being
taken with cancer, and it is proving unsuccessful. Dr. Miller agreed, saying that uterine artery
embolization is a reasonable control group.
Dr. Snyder said the Panel would have to accept that there is no perfect
study, and they would have to rely on symptomatology. There will ultimately have to be a
randomized, controlled trial, as occurred with uterine endometrial
ablation. Dr. Sharts-Hopko supported the
randomization but felt that a second level of consent would be needed if
hysterectomies are involved. Dr. Shirk
pointed out that there never was a trial comparing endometrial ablation to
hysterectomy. Dr. Sharp said that the
importance of randomization is to mitigate the heterogeneity of fibroids.
The Chairman pointed out that the indication the sponsor is
seeking determines the type of trial.
Dr. Cedars said that if the trial is not really about answering a
question, the patients would not want to be randomized. They will want the better treatment. Uterine artery embolization has never been
compared to myomectomy, so there is no basis for making it a standard of
comparison.
Dr. Weeks said that in patients not seeking to maintain
fertility, hysterectomy is still the gold standard, so maybe the best way to
track these women is to see how many, after any noninvasive technique, still
end up having a hysterectomy.
Mr. Pollard asked the Panel, if bleeding were the indication
being pursued, then what would be the control and the role of
randomization? He wanted to know the
Panel’s consensus on whether or not there can be an outcome measure in a single
arm study on bleeding. The Chairman said
that single arm studies would be appropriate in some cases, but the results
would have to be pretty strong. Dr.
Emerson said that randomizing is good for quality of life, but control groups
against the standard of care will be needed in some cases. Dr. Cedars reiterated the perimenopausal
connection and the need to treat patients with hormones first. After that, there has to be randomization,
and the duration of the study depends on the comparator and the endpoints. Dr. Shirk said that a double arm study makes
it possible to get data on overall success as well as complications of the
procedures. Dr. Snyder said that it is
possible to have a randomized controlled trial on abnormal bleeding or
menorrhagia. If the trial is not
randomized and controlled, the criteria will have to be very stringent. Dr. Miller felt that in any trial the
variability would have to be monitored because a disproportion of patients
could easily throw the results off.
Because Question 5 had already been addressed in the
discussion, the Chairman moved to the last question.
Question 6: FDA
has typically asked manufacturers to provide premarket evidence of treatment
success at the 6-month point after surgery, with the understanding that study
subjects will be followed for a minimum of three years. Please discuss the
appropriateness of this pre-market/post-market balance. Does it depend on the
outcome measure itself?
The Chairman pointed out that no sponsor
wants to wait three years after the last patient before seeking approval. However, it is important to know how many
patients need hysterectomies within three years. The three years may be part of a
post-approval study. Dr. Emerson said
that many studies last three years and have 1,000 patients with other
diseases. Dr. Snyder said that safety
and some efficacy can be studied quickly, but the real measure of efficacy is
long term and is the question of whether another procedure is needed before
menopause.
Ms. George pointed out that lengthy trials are preventing
products from being approved in the
The Chairman commented that procedural risks are over in two
days, but the risk of another procedure is a long-term risk. Dr. Cedars said that six months of data is
nearly inconsequential, but three years of data is onerous; she suggested a
minimum of a year with a requirement for post-market follow-up. Dr. Shirk said that the long term follow-up
and failure has not been established even for myomectomy. It may not be appropriate to hold these
devices to a higher standard than the standard of care surgical
procedures. Many of the newer technologies
are coming out of small companies that cannot afford long-term studies. Dr. Miller agreed that no one would argue for
mediocre clinical trials, but if the trials are too big to be done, the
patients don’t get the benefit of the devices.
The point is to get the most benefit with the least risk.
Dr. Emerson pointed out that delaying a hysterectomy for two
years may be all the patient wants in some cases. Dr. Snyder commented that different patients
had different measures of success, but the literature shows that the
incremental increase in failure after one year is very small.
Mr. Pollard clarified that the three-year period mentioned in
the question is post-market. The six
months was pre-market. The Panel
consensus, though, was a one-year pre-market follow-up. These tumors grow slowly, and it would take
that long to know if the tumors are regrowing.
Ms. George asked about the different devices and how they would be
treated in the process, whether these time periods would apply to all device
submissions. Dr. Cedars said that the
devices would be dealt with in terms of their safety and efficacy, but an
indication of bleeding fibroids would require the same duration. The Chairman added that the trial will depend
on the indications being sought.
Mr. Hillard said that NIH spearheaded a symposium last year on
fibroids. They symposium looked at
clinical trial design for drugs to control fibroid-related bleeding and
addressed the issue of validating a more modern tampon or pad for PBLAC. The two endpoints were reduction in bleeding
by the PBLAC score and the need for surgery at some point. The drug study had a placebo group.
Dr. Shirk had questions about safety: whether interrupting the
surface of the uterus, laparoscopically, thermally, or with lasers may lead to
internal adhesions; whether necrotic tumors cause infection; and whether
compressing the uterine arteries will result in ureteral injuries. There can be short-terms complications, but
there may be long-term complications as well.
Dr. Cedars said that most adverse events would manifest within three
months. At a year, most adverse events
would have occurred.
Dr. Snyder expressed concerns about the reproducibility of
pictoral-based assessments of bleeding.
Dr. Sharts-Hopko said that women are not going to weigh or save their
pads. The best you can expect these days
is a pad count and estimate of saturation.
Dr. Cedars said it would be very difficult to get an objective idea of
the amount of bleeding. Dr.
Romero pointed out that objective and subjective measures are a matter of degree. Measurement of change in symptom by a patient
as a quality of life measure is a symptom measure. If the patient believes that less bleeding is
taking place, then the complaint has been addressed. Dr. Sharp suggested looking into literature
on PBLAC, Ruta, and UFS scoring systems to see what is most appropriate.
Mr. Pollard said that FDA has a good track record with PBLAC
scores. He also asked for more comment
on question 5.
Question 5: For
the various study design possibilities, please discuss the definition of study
success, i.e., how good is good enough. Please specifically comment on what
would be the minimally accepted percentage of treated patients who meet the
individual patient success criteria discussed previously, to define the study
as an overall success. In the case of a controlled study, comment on whether
there is a minimum difference between the percentage of successful patients in
each arm that would be needed for the study to be called a success.
Dr. Sharts-Hopko said that the patient
defines success. There are many things
to monitor, but if the patient feels cured, she will not seek further
treatment. Dr. Shirk commented that the
question can only be answered if there is a defined study and a statistical way
to look at things. Dr. Emerson said that
the answer to Question 5 is a matter of cost (in terms of risks and
invasiveness) versus benefit (clinical endpoint).
Dr. Chegini commented that many of these devices are being used
by specialists in other fields, and obstetricians and gynecologists are going
to have to bridge the disciplines to take care of the patients.
Dr. Carey Corrado commented that the studies will need to
produce data that can be put on a label.
The Chairman thanked
the Panel and the FDA for his time as chairman and adjourned the meeting at
2:18 p.m.
I certify that I attended this meeting of the
Obstetrics and Gynecology Devices Panel
on March 28, 2006, and that these minutes
accurately reflect what transpired.
Michael Bailey, Ph.D.
Executive Secretary
____________________________________
I approve the minutes of this meeting as recorded in this summary.
_____________________________
Kenneth Noller, M.D.
Panel Chair
Summary prepared by
Eric Hendrixson
Neal R. Gross & Co., Inc.
(202) 234-4433