1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DEVICES AND
RADIOLOGIC HEALTH
OPHTHALMIC DEVICES PANEL
108TH MEETING
Friday, March 5, 2004
9:00 a.m.
Gaithersburg Holiday
Hotel
2 Montgomery Village
Avenue
Gaithersburg,
Maryland
2
P A R T I C I P A N T
S
Jayne S. Weiss, M.D., Chairperson
Sara M. Thornton, Panel Executive
Secretary
VOTING MEMBERS:
Arthur Bradley, Ph.D.
Michael R. Grimmett, M.D.
Allen C. Ho, M.D.
William D. Mathers, M.D.
Timothy T. McMahon, O.D.
INDUSTRY REPRESENTATIVE:
Ronald E. McCarley
CONSULTANTS:
Neil M. Bressler, M.D.
Jeremiah Brown, Jr., M.D.
Alexander J. Brucker, M.D.
Frederick J. Ferris, M.D.
Leo J. Maguire, M.D.
Janine A. Smith, M.D.
Walter J. Stark, M.D.
FDA PARTICIPANTS:
A. Ralph Rosenthal, M.D.
Malvina B. Eydelman, M.D.
Joseph N. Blustein, M.D.
Don Calogero, M.S.
Gene N. Hilmantel, O.D., M.D.
3
C O N T E N T S
PAGE
Call to Order, Jayne W. Weiss, M.D. 4
Introductory Remarks and Introductions,
Sara M. Thornton, Executive
Secretary 4
Conflict of Interest Statement,
Sara M. Thornton, Executive
Secretary 7
Branch Updates, Karen F. Warburton,
M.S.,
Vitreoretinal and Extraocular Devices
Branch 9
FDA Presentation:
Clear Lens Extraction for the Correction
of
Presbyopia:
Malvina B. Eydelman, M.D., Division
of
Ophthalmic and Ear, Nose and Throat
Devices 11
Joseph N. Blustein, M.D., M.P.H., Division of
Ophthalmic and Ear Nose and Throat
Devices 14
Malvina B. Eydelman, M.D., Division
of
Ophthalmic and Ear, Nose and Throat
Devices 28
Open Public Hearing:
Adrian Glasser, Ph.D., College of
Optometry,
University of Houston 42
Stephen Lane, M.D., University of
Minnesota 51
Randall J. Olson, M.D., University of
Utah
(Letter Read by Ms. Thornton) 65
Panel Deliberations 68
4
1 P R O C E E D I N G S
2
Call to Order
3 DR. WEISS: I
would like to call this
4
meeting of the Ophthalmic Devices Panel to order,
5
and we will have introductory remarks from Sarah
6
Thornton, the Executive Secretary of the Panel.
7 MS. THORNTON:
Good morning. On behalf of
8
the FDA, I would like to welcome you to the 108th
9
meeting of the Ophthalmic Devices Panel.
10 Before we proceed with today's agenda, I
11
have a few short announcements to make.
I would
12
like to remind everyone to sign in on the
13
attendance sheets in the registration area, just
14
outside the meeting room. All
public handouts for
15
today's meeting are available at the registration
16
table. Messages for panel
members and FDA
17
participants, information or special needs should
18
be directed through Ms. Annemarie Williams who is
19
available in the registration area.
The phone
20
number for calls to the meeting area is
21 301-977-8900.
22 In consideration of the panel, the sponsor
23
and the agency, we ask that those of you with cell
24
phones and pagers either turn them off or put them
25
on vibration mode while in this room, and make your
5
1
calls outside the meeting area.
2 Lastly, will all meeting participants
3
please speak clearly into the microphone and give
4
your name so that the transcriber will have an
5
accurate recording of your comments?
6 At this time I would like to extend a
7
special welcome and introduce to the public, the
8
panel and the FDA staff two new panel consultants
9
who are with us at the table today for the first
10
time.
11 On my right, Dr. Neil Bressler, Professor
12
of Ophthalmology, with an international referral
13
practice in the Retinal Vascular Center at the
14
Wilmer Eye Institute of The Johns Hopkins
15
University School of Medicine; and Dr. Jeremiah
16
Brown, Jr., who is the director of Ophthalmology
17
Research at the Walter Reed Army Institute of
18
Research Laboratory at Brooks Air Force Base in San
19
Antonio, in addition to maintaining a private
20
retina practice with Ophthalmology Associates of
21
San Antonio. Welcome, gentlemen.
22 Will the remaining panel members please
23
introduce themselves, beginning with Rick McCarley?
24 MR. MCCARLEY:
Good morning. My name is
25
Rick McCarley. I am President of
Ophtec and I am
6
1
the industry representative.
2 DR. BRUCKER:
Alexander Brucker,
3 Philadelphia,
Pennsylvania, Professor of
4
Ophthalmology at the University of Pennsylvania
5
Scheie Eye Institute.
6 DR. FERRIS:
Rick Ferris, I am the head of
7
the Division of Epidemiology and Clinical Research
8
at the National Eye Institute.
9 DR. BRADLEY:
Arthur Bradley, Professor of
10
Vision Science, Indiana University.
11 DR. MCMAHON:
Tim McMahon, Professor of
12
Ophthalmology, Department of Ophthalmology,
13
University of Illinois in Chicago.
14 DR. WEISS:
Jayne Weiss, Professor of
15
Ophthalmology and Pathology, Kresge Eye Institute,
16
Wayne State University, Detroit.
17 DR. GRIMMETT:
Michael Grimmett, Bascom
18
Palmer Eye Institute, University of Miami.
19 DR. MATHERS:
Bill Mathers, Professor of
20
Ophthalmology at Oregon Health Sciences University.
21 DR. HO: Good
morning. Allen Ho,
22
vitreoretinal surgeon, Wills Eye Hospital, Thomas
23 Jefferson University.
24 DR. SMITH:
Janine Smith, Deputy Clinical
25
Director of the National Eye Institute.
7
1 DR. BRESSLER:
Neil Bressler, already
2
introduced.
3 DR. BROWN:
Jeremiah Brown.
4 DR. STARK:
Walter Stark, Professor of
5
Ophthalmology, Wilmer Eye Institute, Baltimore,
6
Maryland.
7 DR. MAGUIRE:
Leo Maguire, Associate
8
Professor, Mayo Clinic, Rochester, Minnesota.
9 DR. ROSENTHAL:
Ralph Rosenthal, Division
10
Director, Ophthalmic and ENT Devices.
11 MS. THORNTON:
Thank you. I would like to
12
note for the record that the panel consumer
13
representative, Ms. Glenda Such, will not be in
14
attendance today due to illness.
Thank you, Jayne.
15 Conflict of Interest Statement
16 I would now like to read the conflict of
17
interest statement for today's meeting.
The
18
following announcement addresses conflict of
19
interest issues associated with this meeting, and
20
is made part of the record to preclude even the
21
appearance of an impropriety.
22 To determine if any conflict existed, the
23
agency reviewed the submitted agenda for this
24
meeting and all financial interests reported by the
25
committee participants. The
conflict of interest
8
1
statutes prohibit special government employees from
2
participating in matters that could affect their or
3
their employers' financial interests.
However, the
4
agency has determined that participation of certain
5
members and consultants, the need for whose
6
services outweighs the potential conflict of
7
interest involved, is in the best interests of the
8
government.
9 Therefore, a waiver has been granted to
10
Dr. Alexander Brucker for his interest in a firm at
11
issue that could potentially be affected by the
12
panel's recommendations. The
waiver allows him to
13
participate fully in today's deliberations. Copies
14
of this waiver may be obtained from the agency's
15
Freedom of Information Office, Room 12A-15 of the
16
Parklawn Building.
17 We would like to note for the record that
18
the agency took into consideration certain matters
19
regarding Drs. Alexander Brucker, Neil Bressler,
20
Frederick Ferris, Michael Grimmett, Allen Ho and
21
Jayne Weiss. They reported
interests in firms at
22
issue but in matters not related to today's agenda.
23
The agency has determined, therefore, that they may
24
participate fully in all discussions.
25 In the event that the discussions involve
9
1
any other products or firms not already on the
2
agenda for which an FDA participant has a financial
3
interest, the participant should excuse himself or
4
herself from such involvement and the exclusion
5
will be noted for the record.
6 With respect to all other participants, we
7
ask in the interest of fairness that all persons
8
making statements or presentations disclose any
9
current or previous financial involvement with any
10
firm whose products they may wish to comment upon.
11
Thank you, Jayne.
12 DR. WEISS:
Thank you. We are going to
13
now have branch updates, Karen Warburton.
14 Branch Updates
15 MS. WARBURTON:
Good morning. I would
16
like to present one item of interest from our
17
Branch. One of the device types
that the VEDB
18
reviews is the ophthalmic sponge, which is used
19
during LASIK surgery. We have
recently become
20
aware of Medical Device Reports, or MDRs, that
21
identified an association between ophthalmic
22
sponges and diffuse lamellar keratitis.
Testing of
23 a
sample of ophthalmic sponges from a lot
24
associated with a cluster of DLK cases showed
25
significantly higher levels of bacterial endotoxin
10
1
than a different lot. Additional
MDRs have also
2
reported an association between microkeratomes and
3
DLK, although most of those reports did not
4
implicate endotoxin per se.
5 Endotoxin has been shown to cause DLK in a
6
rabbit model and there have been reports in the
7
literature implicating endotoxin from sterilizer
8
water reservoirs as a cause of DLK outbreaks.
9
Additionally, a variety of other etiological
10
factors have been suggested.
However,
11
endotoxin-contaminated ophthalmic sponges have not
12
previously been identified as a possible cause of
13
DLK. Endotoxin-contaminated
water used during
14
device manufacture is a potential source.
15
Historically, FDA has not required that ophthalmic
16
sponges or other devices used in LASIK surgery be
17
pyrogen or endotoxin free, and they are typically
18
not labeled as such, although many may, in fact, be
19
endotoxin free.
20 Our Branch is working with other Center
21
offices to make the ophthalmic community aware of
22
this potential cause of DLK through letters to
23
professional organizations and letters to the
24
editor in journals which we anticipate will be
25
published in the near future. We
hope to encourage
11
1
reporting of DLK to FDA through MDR reporting, and
2
to stimulate both user and FDA investigation into
3
these outbreaks so that we can better understand
4
the role that ophthalmic devices and endotoxin in
5
particular play in DLK, and make changes in our
6
product review policies if necessary.
That
7
concludes my update. Are there
any questions?
8 DR. WEISS:
Seeing no questions, thank you
9
very much, Karen. We will now
begin the open
10
committee session with the general issues
11
discussion and the FDA team presentation. Dr.
12
Eydelman?
13 FDA
Team Presentation
14 DR. EYDELMAN:
Good morning.
15 [Slide]
16 Today's discussion is centered around
17
clear lens extraction for the correction of
18
presbyopia. I want to thank Dr.
Blustein, Don
19
Calogero and Gene Hilmantel for organizing today's
20
presentation and preparing all the materials.
21 [Slide]
22 Clear lens extraction--or CLE as we will
23
be referring to it for the rest of the day--for the
24
correction of presbyopia is an intraocular surgical
25
procedure where non-cataractous lens is removed and
12
1
replaced with a multifocal intraocular lens,
2
allowing for both distance and near vision. The
3
sole purpose of this procedure is for refractive
4
correction.
5 [Slide]
6 There are several points I wanted to make
7
sure panel members are clear on.
CLE is not
8 currently
approved in U.S. for any indication. It
9
has been performed, as all of you know, as an
10
off-label practice for several years but mainly in
11
eyes with high refractive errors.
12 [Slide]
13 There are currently no standards or
14
guidances available for clear lens extraction with
15
IOL implantation.
16 [Slide]
17 There is currently only one multifocal IOL
18
approved in U.S., but there are quite a few under
19 investigation. Only two IOLs are approved for
20
improving near vision acuity in presbyopic
21
patients, and that is the AMO Array and the CMC
22
Vision. Several different
devices utilizing quite
23
various approaches are under investigation. Again,
24
there are no standards or guidances for devices
25
solely intended for the correction of presbyopia.
13
1 [Slide]
2 An estimated 1.5 billion people worldwide
3
have presbyopia. Therefore,
devices approved for
4
the correction of presbyopia will have a very
5
significant public health impact.
6 [Slide]
7 The challenge that faces us today is in
8
trying to design a study which will be least
9
burdensome for establishing safety and efficacy of
10
the device for the correction of presbyopia while
11
making sure that the significance to public health
12
impact due to improper trial design is considered.
13 [Slide]
14 We want to make sure that we address all
15
the appropriate aspects of the appropriate study
16
design. So, today we will ask
for your
17
consideration on the control population;
18
inclusion/exclusion criteria; acceptable adverse
19
event rates; sample size; study duration; variables
20
to be investigated; efficacy endpoints and quality
21
of life assessment.
22 [Slide]
23 The goal, of course, is designing an
24
appropriate clinical trial for evaluation of clear
25
lens extraction for the correction of presbyopia.
14
1
The first step in pursuing that goal was
2
identification of all relevant adverse events and
3
their anticipated time course.
In order to address
4
that, we did quite an extensive literature search
5
which Dr. Blustein will summarize for you.
6 [Slide]
7 DR. BLUSTEIN:
Initially we looked for
8
studies that related specifically to clear lens
9
extraction for presbyopia. There
were very few
10
articles that addressed this topic.
There were two
11
that we found, Dick and associates and Packer and
12
associates, that dealt with clear lens extraction
13
for presbyopia. Both studies
were using the Array
14
multifocal IOL.
15 [Slide]
16 Dick and associates--their study was a
17
prospective study with 25 patients.
They were
18
bilateral CLE with MIOL. The
average patient age
19
was 51, with a range of 44-62.
The preop spherical
20
equivalent ranged from minus 25.5 to plus 5.75
21
diopters. Follow-up was at 6
months and the
22
outcomes for efficacy were very good, 100 percent
23
binocular uncorrected visual acuity of 20/30 and J4
24
or better. However, 48 percent
of the patients
25
complained of star bursts and 36 percent complained
15
1
of halos.
2 [Slide]
3 Packer and associates, in a retrospective
4
study of 68 eyes and 36 patients--their study was
5
not limited to just clear lens extraction but 34
6
percent of the eyes had received additional
7
procedures for astigmatism. The
average age was 58
8
years old and the range was from 45-81.
Preop
9
spherical equivalent ranged from minus 7.5 to plus
10
6.5 diopters. Follow-up was at 3
and 6 months.
11
The outcomes--again, there was good efficacy with
12
94 percent binocular uncorrected visual acuity of
13
20/40 and J5 or better. Close to
6 percent had
14
symptomatic posterior capsular opacities requiring
15
YAG capsulotomies. There were no
complication
16
rates and there were no reports or assessment of
17
visual symptoms.
18 [Slide]
19 Clear lens extraction with monofocal
20
IOLs--because there was limited information for the
21
multifocals we looked at what was done with
22
correcting other refractive procedures with clear
23
lens extraction so we looked at three areas for
24
ametropia, hyperopia and myopia.
25 [Slide]
16
1 Vicary and associates, in a retrospective
2
study of 138 cases with average patient age of
3
close to 49 years of age, ranging from 22-69 years
4
of age, with a range of preop spherical equivalent
5
of minus 23.75 to plus 11.62 diopters, with an
6
average follow-up time of 5 months, with a range of
7
2-26 months, reported on the following outcomes:
8
They had uncorrected visual acuity at 3 months with
9
90 percent at 20/40 or better and close to 50
10
percent had 20/20 or better.
Retinal detachment at
11 5
months, there was one case so that gave a rate of
12
0.7 percent. Uveitis, again one
case with the same
13
rate. Posterior capsular
opacification requiring
14
YAG capsulotomies was at 8 percent.
Additional
15
refractive surgeries were performed in 7 cases.
16 [Slide]
17 For clear lens extraction for hyperopia
18
there were several studies that were performed in
19
U.S., England, Belgium, India and Greece. They
20
overall reported good efficacy in these studies.
21
The sample sizes were relatively small, ranging
22
from 18 to 50 eyes. Patient age
ranges were from
23
19-86, and this is across all these studies. The
24
preop spherical equivalent ranged from plus 2.75 to
25
plus 13 diopters. The follow-up
was anywhere from
17
1
1-60 months in these patients.
2 [Slide]
3 The complications reported for the clear
4
lens extraction for hyperopia collectively in these
5
studies were that for posterior capsular
6
opacification requiring YAG capsulotomy ranged from
7
5.6 percent to 54 percent in these studies.
8
Posterior capsular tears at the time of surgery
9
ranged from close to 3 percent to a little over 5
10
percent. Two cases required IOL
exchange. Then,
11
there were single case events reported of iris
12
prolapse, iridodialysis, corneal burn and malignant
13
glaucoma. The malignant glaucoma
case occurred two
14
years after implantation.
Endothelial cell loss
15
was reported for one study after 12 months at 7.38
16
percent.
17 [Slide]
18 Then we looked at clear lens extraction
19
for high myopia. There are
several reported
20
studies with high efficacy. The
problems with
21
these studies is that there are short follow-up
22
times that are associated with them and also
23
exclusion of lost to follow-up on patients.
24 [Slide]
25 Colin and associates had a 7-year
18
1
follow-up of their study of clear lens extraction
2
for high myopia. There were 52
eyes in 30
3
patients. Preop spherical
equivalent average was
4
minus 16.9 diopters and the axial length in 64
5
percent was greater than 29 mm.
Average patient
6
age was 36, a little over 36 years of age, with a
7
range of 22-51 years of age.
They had performed
8
laser pre-treatments on anyone who had suspicious
9
lesions for future retinal detachments, treating
10 lattice,
retinal tears and retinal holes. The
11
results of this study showed that close to 60
12
percent were within 1 diopter of emmetropia and
13
approximately 85 percent were within 2 diopters of
14
emmetropia.
15 [Slide]
16 Colin and associates reported the retinal
17
detachment rate at 4 years and then again at 7
18
years. At 4 years it was 2
percent and at 7 years
19
it was 8.1 percent. This points
out the importance
20
that retinal detachments can occur later in the
21
postop period.
22 [Slide]
23 In this study 75 percent of the retinal
24
detachment had YAG capsulotomies prior to the
25
retinal detachments. One eye had
YAG one year
19
1
before the retinal detachment and two eyes had YAG
2
two years before the retinal detachment. In the
3
four eyes that had retinal detachments the best
4
corrective visual acuity ranged from 20/30 to
5
20/200 and the visual acuity in the fellow eye
6
ranged from 20/30 to 20/100 in the untreated eye.
7 [Slide]
8 The slide on the right shows the posterior
9
opacification with YAG capsulotomies.
At 4 years
10
it was approximately 37 percent and 61 percent
11
after 7 years. So, again, this
is to illustrate
12
that complications of posterior opacification can
13
occur beyond the follow-up time, short follow-up
14
time. So, after 7 years there
was a significant
15
number that also had complications of
16
opacification.
17 [Slide]
18 The mean time to YAG in this study was a
19
little bit over 48 months, ranging from 9-75
20
months. Close to 37 percent
within 4 years of
21
clear lens extraction had significant posterior
22
capsular opacification and 61 percent within the 7
23
years. The odds ratio of retinal
detachment after
24
clear lens extraction and YAG versus no YAG was
25
2.0. Other complications that
were reported in
20
1
Colin's study were subfoveal choroidal
2
neovascularization in one eye which occurred 9
3
months after surgery, and there was a decrease in
4
best corrected visual acuity in that eye from 20/50
5
to 20/200.
6 [Slide]
7 Ripandelli and associates were reporting
8
from the refractive surgeons studies.
They were
9
reporting from the retinal surgeons perspective.
10
They reported on retinal detachment secondary to
11
clear lens extraction for high myopia.
they saw 53
12
eyes in their practice. The
preop spherical
13
equivalent average was minus 19.5 diopters, ranging
14
from minus 14 to minus 29.
Patient age was an
15
average of 37.5, ranging from 25-58 years of age.
16
This is in Italy, this practice.
Laser pre-clear
17
lens extraction was performed in close to 58
18
percent of these eyes. The time
after clear lens
19
extraction to the retinal detachment average was
20
2.25 years and ranged anywhere from 1 month to 4
21
years. YAG capsulotomies had
been performed in a
22
little bit over 25 percent of these patients.
23
Then, macular involvement was in 100 percent of the
24
eyes that had been operated on.
25 [Slide]
21
1 Twelve eyes were lost to follow-up because
2
they didn't come back for surgery even though that
3
was recommended. For retinal
detachment repair, 88
4
percent had the retina reattached; 41.5 percent had
5
proliferative vitreoretinopathy; 34 percent had
6
posterior retinal breaks. The
results are that 22
7
percent had best corrected visual acuity of 20/60
8
or better. One patient had hand
motion in one eye
9
and 20/100 in the other. The
pre-clear lens
10
extraction visual acuity in this patient was 20/20
11
and 20/25.
12 [Slide]
13 O'Brien and associates reported that for
14
clear lens extraction for high myopia the efficacy
15
is certainly encouraging, that this seems to be
16
very beneficial in terms of correcting the
17
refractive error. However, the
potential
18
complications still outweigh the risks.
19 [Slide]
20 Literature review for clear lens
21
extraction--there was only one study with long-term
22
follow-up. That was the Colin
study that followed
23
for 7 years. The rates of
retinal detachment
24
continue to increase postop, 2 percent at 4 years
25
and then 8 percent at 7 years.
Lack of long-term
22
1
retinal detachment rates post clear lens extraction
2
is a concern. So, we did a
little literature
3
search on retinal detachment rates post cataract
4
extraction.
5 [Slide]
6
About 40 percent of all
retinal
7
detachments occur post cataract extraction.
8
Patient-dependent risk factors include age, gender,
9
refractive state, fellow eye, status of the
10
posterior vitreous. Those are
patient-dependent
11
risk factors.
12 [Slide]
13 Surgeon-dependent risk factors include
14
surgical technique, whether it is intracapsular or
15
extracapsular, phacoemulsification and also
16
incision size, capsulotomy and maintaining anterior
17
chamber depth. Intraoperative
complications are
18
also risk factors--torn posterior capsule or
19
vitreous loss.
20 [Slide]
21 Then, postoperative risk factors include
22
trauma and YAG capsulotomy.
23 [Slide]
24 Norregaard and associates had a
25
population-based Danish study which looked at all
23
1
cataract inpatient surgeries done from 1985 to 1987
2
with 4-6 years follow-up and patient age of 50 or
3
over. They used a reference
group of a cohort that
4
was age matched, gender matched and had no previous
5
intraocular surgery.
6 [Slide]
7 The 4-year retinal detachment risk after
8
cataract surgery for various surgical techniques
9
was shown to be 3.2 percent for extracapsular
10
without IOL; 2.8 percent for intracapsular cataract
11
extraction without IOL; and 0.93 percent for
12
extracapsular without IOL. The
reference group had
13
retinal detachment rate of 0.21 percent.
14 [Slide]
15 The 4-year retinal detachment risk after
16
extracapsular cataract extraction with IOL was
17
stratified by age. There were
increasing rates
18
with decreasing age, 2.43 percent for the age group
19
of 50-59 years of age; 60-69 years of age, 1.51
20
percent; 0.82 percent for 70-79 years of age; and
21
80 and above was 0.47.
22
[Slide]
23 This relative risk for retinal detachment
24
stratified by age, with the reference group having
25
no intraocular surgery, shows that there is a
24
1
significant relative risk in the younger age
2
groups. In the 50-59 group, they
are over 20 times
3
more likely to have a retinal detachment having had
4
surgery; for 60-69 they are 12.5 times more likely
5
to have retinal detachment; 70-79, close to 7 times
6
more likely; and even 80 and older still, close to
7 4
times more likely to have retinal detachment when
8
no surgery was performed.
9 [Slide]
10 Javitt and associates, did a U.S.
11
population-based study looking at all Medicare
12
beneficiaries having cataract extraction in the
13
year 1984, with a sample size of over 300,000 and
14
they excluded the younger age Medicare
15
beneficiaries and only included the 66 and older
16
group. Extracapsular extraction
was done in 60
17
percent of these patients; intracapsular was done
18
in 31 percent; and phacoemulsification in 9
19
percent. They followed this in
the database for
20
rehospitalization for retinal detachments over 4
21
years.
22 [Slide]
23 In their study, they showed that the risk
24
factors were dependent on race, with whites being
25
1.7 times more likely to have a retinal detachment
25
1
than Blacks and with the various surgical
2
techniques the intracap having the greatest risk
3
and phacoemulsification the lowest.
The younger
4
age is also at greater risk for retinal detachments
5
compared to the older, and we will go into that a
6
little bit more.
7 [Slide]
8 For 4-year retinal detachment risk after
9
cataract surgery stratified by age, they found 2.2
10
percent for 65-59 years of age patients; 1.3
11
percent for 70-79 year-old patients; 0.6 percent
12
for 80-89; and 0.2 percent for 90 and above.
13 [Slide]
14 When you look at the relative risk, the
15
65-69 year age group were 18 times more likely to
16
have retinal detachment than the no surgery group;
17
70-79 years old, close to 11 times more likely to
18
have retinal detachment; 80-89, 5 times more
19
likely; and 90 or above, 1.67 times more likely to
20
have retinal detachment.
21 [Slide]
22 Javitt did another study. This was based
23
on a 5 percent sample of Medicare beneficiaries.
24
They looked at inpatient and outpatient surgeries
25
between 1986 and 1987. The
sample size was over
26
1
57,000, and they looked at 3-year follow-up for
2
retinal detachment.
3 [Slide]
4 The cumulative 3-year retinal detachment
5
rate was 0.81 percent, which was a rate similar to
6
the previous inpatient study.
Also, they showed
7
that younger patients were more at risk than older
8
patients.
9 [Slide]
10 This is from the 3-year retinal detachment
11
risk after extracapsular cataract extraction,
12
showing 0.95 percent for the 65-69 year-old group;
13
0.51 percent for the 70-79 year-olds; 0.24 percent
14
for the 80-89 year-olds; and 0.08 percent for the
15 90 and above.
16 [Slide]
17 Looking at the slide on your right,
18
summarizing the Danish study and the earlier Javitt
19
study, they found one-year rates for retinal
20
detachment with extracapsular with IOL and for the
21
Danish study it was 0.42 percent and the 4-year
22
rate was 3.2 percent for extracapsular without IOL
23
and then 0.93 percent for extracapsular with IOL.
24 In the Javitt study the one-year rate for
25
combining extracapsular cataract extraction whether
27
1
it was with or without IOL was 0.3 percent and for
2
phacoemulsification it was 0.4 percent.
The 4-year
3
rate was 0.9 percent for extracapsular cataract
4
extraction and 1.17 percent for
5
phacoemulsification.
6 [Slide]
7 The relative risk for retinal detachment
8
at one year in the Danish study, extracapsular
9
cataract extraction with IOL was 14 times more
10
likely to have retinal detachment than no surgery.
11
At 4 years, extracapsular cataract extraction with
12
IOL was 26.67 times more likely to have retinal
13
detachment than no surgery; and extracapsular
14 cataract extraction with IOL was 7.75 times
more
15
likely.
16 In the U.S. study at one year
17
extracapsular cataract extraction was 10 times to
18
have a retinal detachment, and with
19
phacoemulsification it was 13.3 times more likely
20
to have a retinal detachment. At
4 years the
21
relative risk for retinal detachment with
22
extracapsular cataract extraction was 7.5 times and
23
for phacoemulsification was 9.75 times.
24 [Slide]
25
Rowe and associates
reported on cumulative
28
1
retinal detachment rates after extracapsular
2
cataract extraction and phacoemulsification. It
3
was a population-based study in Olmstead County,
4
Minnesota. It was an incidence
study. They looked
5
at retinal detachment diagnosed between 1976 and
6
1995. The retinal detachment
rates were adjusted
7
for age and gender and they were compared with
8 non-surgical retinal
detachment rates.
9 [Slide]
10 The cumulative retinal detachment rates
11
after extracapsular cataract extraction and
12
phacoemulsification at 2 years was 0.36 percent
13
compared to 0.034 percent with no surgery. At 5
14
years it was 0.77 percent compared to 0.13 percent
15
with no surgery. At 10 years it
was 1.29 percent
16
compared to 0.25 percent with no surgery.
17 [Slide]
18 Looking at this as relative risk, at 2
19
years it is 10.59 times more likely to have a
20
retinal detachment with cataract surgery; at 5
21
years it was 5.92 times more likely; and at 10
22
years it was 5.16.
23 [Slide]
24 DR. EYDELMAN:
In light of the literature
25
summary that you just heard, the first question we
29
1
would like you to consider is do you recommend a
2
control population for studies of clear lens
3
extraction for the correction of presbyopia, or do
4
you believe that the study subject's own
5
preoperative data is sufficient for comparison?
6 [Slide]
7 If you do recommend a control population,
8
which one of the following do you believe to be
9
appropriate? Is it historical
control, active
10
control or some other control?
Active control
11
would imply concurrent enrollment in a study of
12
subjects with no previous ocular surgery. For
13
historical control that you would obtain from the
14
literature, there are several options, subjects'
15
status post CLE for correction of presbyopia or
16
those that have had a composite of all different
17
refractive indications; subjects' status post
18
cataract extraction or those that had no previous
19
ocular surgery. Those are,
obviously, all choices
20
we would like you to consider.
21 [Slide]
22 Any time we define an appropriate study
23
population for the investigation the real issue is
24
identifying patients for whom risk/benefit
25
assessment warrants enrollment in such a study.
30
1 [Slide]
2 Therefore, the question we ask you is
3
should the clinical study inclusion/exclusion
4
criteria limit subject enrollment based on the
5
criteria listed below? If yes,
we would like you
6
to discuss the appropriate ranges of each limiting
7
criteria for inclusion in the study.
8 [Slide]
9 Under (a) is refractive error and axial
10
length, and we would like you to consider each one,
11
the hyperopia and its associated refractive range;
12
emmetropia; myopia with its range; (b) subject's
13
age.
14 [Slide]
15 (c) Degree of accommodative loss, and in
16
that discussion we would like you to consider based
17
on what measurement you are making your
18
recommendations; (d) preoperative endothelial cell
19
count; and (e) any other factors, such as BCVA.
20 [Slide]
21 As you heard from Dr. Blustein, there are
22
several numbers that are reported in the literature
23
but all the literature essentially concurs that
24
subjects with no surgery have much less chance than
25
those that do undergo a lens extraction.
31
1 [Slide]
2 With that in mind, we would like you to
3
consider what should be the primary safety endpoint
4
for the study?
5 [Slide]
6 Another consensus from the literature is
7 that the younger
subjects do, indeed, have higher
8
cumulative RD rates and that is basically due to
9
the vitreoretinal interface characteristics and the
10
fact that the risk continues to increase over time
11
and these subjects have essentially a greater
12
number of years left to life after the lens
13
extraction.
14 [Slide]
15 So, is retinal detachment primary safety
16
endpoint?
17 [Slide]
18 After clear lens extraction with MIOL
19
subjects might experience visual symptoms requiring
20
IOL exchange. Therefore,
endothelial cell
21
densities should be adequate to withstand
22
additional surgery. From the
literature review you
23
have heard only one number, 7.38 percent
24
endothelial cell loss at 12 months after CLE.
25
However, these losses are really consistent with
32
1
operative losses themselves.
2
[Slide]
3 Several years ago Don Calogero, myself and
4
Dr. Aresnoff, from Toronto, performed a
5
meta-analysis of a literature review to try to
6
determine what is the operative endothelial cell
7
loss secondary to cataract surgery.
There we
8
determined that 8.9 percent endothelial cell loss
9
is seen secondary to extracap and 7.4 secondary to
10
phaco. These are losses that
were secondary to
11
operative loss itself, i.e., the range was 2-6
12 months.
13 [Slide]
14 There is no long-term data on endothelial
15
cell loss after clear lens extraction.
16
Furthermore, there is very limited data on
17
long-term loss after cataract surgery.
We all know
18 from
the last several panel meetings that Bourne
19
et. al. reported 0.6 percent CLE loss for eyes
20
without any surgery. However, I
don't think all of
21
you might be aware of the fact that Bourne has also
22
performed a study showing that after cataract
23
surgery itself there is a 2.5 percent cell loss
24
that continues annually. Now,
this was at 10-year
25
follow-up of a rather small cohort, 64 eyes, and
33
1
surgeries were performed from '76 to '82, both
2
extracap and intracap, and some of the subjects
3
were left aphakic. So, the
accuracy of that number
4
with respect to modern surgery is questionable, but
5
the fact that there is continuous loss secondary to
6
cataract extraction itself seems to be implicit.
7 [Slide]
8 In light of that, is endothelial cell loss
9
perhaps a primary safety endpoint, or if not a
10
primary, should it be a safety endpoint?
11 [Slide]
12 Once you discuss what should be the
13
primary safety endpoint, we would like you to
14
concentrate on the acceptable adverse event rate
15
associated with this safety endpoint.
16 [Slide]
17 The next question that we would like you
18
to consider is sample size and follow-up
19
appropriate for clear lens extraction studies. Not
20
to give you a blank screen, we did several sample
21
size assessments so you have something to work
22
with.
23 The slide on the left summarizes
24
statistics that we ran for the sample sizes that
25
would be required for maximum allowable RD rate per
34
1
year. Here we assume a
historical control rate of
2
0.01 percent annual RD. So, in
the first column we
3
have different study duration options, 1 year, 2
4
years, 3 years. Just to give you
an example, if we
5
assume that the maximum allowable RD rate per year
6
should be 0.3 percent, a study design would require
7
321 subjects. That is how this
table reads. If
8
you have any questions later I can describe it
9
further.
10 [Slide]
11 We also ran sample size statistics for
12
endothelial cell loss. There are
two tables, this
13
and the next slide. This one is
assuming a fixed
14
historical rate of 0.6 percent annual cell loss.
15
Again, in the first column you have one, two or 3
16
year study duration. Across,
1,000, 1,200, 1,400
17
and 1,500 are some of the cell densities that we
18
assumed for you to choose from as the minimum cell
19
density that you would like subjects to have at age
20
75. As a reference, down below,
in the yellow, I
21
put down that the normal ECD at age 75 is 2,400
22
with a standard deviation of 500.
So, once again
23
just to try to explain to you how this table works,
24 if
you say that you would like for a subject at age
25
75, after having clear lens extraction performed
35
1
somewhere in their 40s, to end up with 1,200 cells,
2
for a one-year study that would require 319
3
subjects and for a three-year study only 26
4
subjects.
5 [Slide]
6 As I showed you before, this is the same
7
table but now assuming active control, i.e., you
8
would enroll patients who are not operated and you
9
measure their cell loss. With
the same examples,
10
one year for 1,200 would be 638 and for three years
11
it would be 48.
12 [Slide]
13 So, the question is in order to adequately
14
determine the rates of all the adverse events and
15
complications of concern, what do you feel is the
16
appropriate sample size and follow-up period for a
17
CLE study for the correction of presbyopia prior to
18
the submission of the PMA?
19 [Slide]
20 I stress "prior" because the next question
21
deals with post-market studies.
To clarify, the
22
post-market process can detect, identify and
23
describe new or previously undetected medical
24
device hazards. It also has the
advantage of using
25
real-world medical device experience to confirm the
36
1
safety profile of the device that was established
2
in the pre-market submission and it could be a
3
condition of approval.
4 [Slide]
5 In light of that, do you believe a
6
post-market study is indicated?
If so, what is the
7
appropriate type of study, sample size and length
8
of follow-up for such a study?
9 [Slide]
10 Acceptable adverse event rates for
11
posterior chamber IOLs at one year following
12
cataract extraction are in the FDA grid. The
13
updated FDA adverse event rates are listed for you
14
on the left, and I will spare you going through
15
them. Are these rates applicable
for correction of
16
presbyopia in non-cataractous eyes for CLE at one
17
year postop? Again, we are
comparing one year to
18
one year but adverse events that were historically
19
acceptable after cataract surgery now to eyes which
20
have not had cataracts.
21 [Slide]
22 Should the acceptable adverse event rates
23
be adjusted for the study duration recommended? If
24
yes, how? Furthermore, do
additional adverse
25
events need to be collected? If
so, what should be
37
1
their acceptable rates?
2 [Slide]
3 FDA believes that all multifocal IOLs'
4
safety and efficacy profiles will have to be
5
established in a cataractous population prior to
6
initiation of a clinical trial in a non-cataractous
7 population. MIOL
performance in a cataractous
8
population will, therefore, be known for all tests
9
and sub-studies outlined in ANSI draft standards
10
for MIOLs.
11 [Slide]
12 On the slide on the left I summarized for
13
you in the first column all the measurements that
14
are recommended to be performed on all study
15
populations. In the column on
the right are those
16
that are done in sub-studies.
Just to clarify, it
17
is best spectacle corrected visual acuity at
18
distance; near visual acuity with distance
19
correction; uncorrected visual acuity at distance;
20
uncorrected visual acuity at near; pupil size; lens
21
stability; and subject survey.
The sub-studies are
22
defocus curves; fundus visualization; far contrast
23
sensitivity; and functional performance.
24 [Slide]
25 Which sub-studies do you recommend for
38
1
inclusion in the clear lens extraction protocol for
2
evaluation of performance in this non-cataractous
3
population? A) is functional
performance and the
4
functional performance study determines deficits in
5
functional vision secondary to optical effects or
6
multifocal IOLs. An example is a
driving
7
simulation study which was performed for MIOLs.
8 B) is contrast sensitivity and the current
9
recommendation is for grading contrast sensitivity
10
tests to assess threshold for spatial gradings.
11 C) is defocus curves and defocus
12
evaluation comparing clinical performance to the
13
theoretical lens design. What is
done is that a
14
subject's best spectacle corrected visual acuity at
15
distance is obtained for the subject, and then the
16
subject is defocused in 0.5 diopter steps to minus
17 5
diopters.
18 D) is fundus visualization and the current
19
recommendation is for the investigators to rate the
20
clarity of the retinal image through multifocal
21
versus monofocal IOLs.
22 Then there is the endothelial cell
23
evaluation and I think you all know about that by
24
now, and any others that you might recommend.
25 [Slide]
39
1 The only current performance efficacy
2
endpoint for aphakic posterior chamber IOLs, from
3
the FDA grid once again, is post-operative BCVA of
4
20/40 or better in 92.5 percent of the subjects.
5
Is this applicable to non-cataractous eyes
6
undergoing CLE for the correction of presbyopia?
7 [Slide]
8 Question 7 B), are the predictability--75
9
percent of eyes with MRSE plus/minus 1 diopter and
10
50 percent with MRSE plus/minus 0.5 diopter and
11
UCVA endpoint of 85 percent with 20/40 or better,
12
outlined in FDA's draft guidance for refractive
13
implants, applicable for this scenario?
14 [Slide]
15 Do we need to establish a performance
16
efficacy endpoint for UCVA at near in this
17
population of subjects who are undergoing surgery
18
for the correction of presbyopia?
If yes, what do
19
you recommend?
20 [Slide]
21 What additional performance efficacy
22
endpoints, if any, need to be set?
23 [Slide]
24 Something that you all need to consider is
25
whether a general population of presbyopes without
40
1
cataracts will be tolerant of potential optical
2
aberrations associated with MIOLs.
3 [Slide]
4 How do you recommend that we evaluate
5
patient's quality of life issues?
6 [Slide]
7 There are several questionnaires which are
8
validated and recommended in our ANSI standards,
9
Javitt, Vitale, Schein and NEI refractive. If you
10
can make a specific recommendation about the
11
applicability of these questionnaires or
12
combination of them, we would greatly appreciate
13
it. This concludes our
presentation.
14 DR. WEISS: Dr.
Eydelman and Dr. Blustein,
15
your presentation was absolutely superb and I hope
16
the clarity of your questions can be met by the
17
panel's answer to your questions.
18 DR. EYDELMAN:
Thank you.
19 DR. WEISS:
Thank you very much. We are
20
now going to open the open public hearing session.
21
Before we do, there is a statement that the FDA
22
requires me to read. Both the
Food and Drug
23
Administration and the public believe in a
24
transparent process for information gathering and
25
decision-making. To ensure such
transparency at
41
1
the open public hearing session of the advisory
2
committee meeting, FDA believes that it is
3
important to understand the context of an
4
individual's presentation. For
this reason, FDA
5
encourages you, the open public hearing speaker, at
6
the beginning of your written or oral statement to
7
advise the committee of any financial relationship
8
that you may have with a sponsor its product and,
9
if known, its direct competitors.
For example,
10
this financial information may include the
11
sponsor's payment of your travel, lodging or other
12
expenses in connection with your attendance at the
13
meeting. Likewise, FDA
encourages you at the
14
beginning of your statement to advise the committee
15
if you do not have such financial relationships.
16
If you choose not to address this issue of
17
financial relationships at the beginning of your
18
statement it will not preclude you from speaking.
19 We have two speakers today. I will ask
20
Dr. Adrian Glasser, Associate Professor at the
21
College of Optometry, University of Houston, to
22
come forward for his presentation.
I will inform
23
members of the panel that there will be an
24
opportunity to ask questions, both to the FDA team
25
as well as the open public hearing presenters, at
42
1
the beginning of the panel deliberations.
2 Open Public Hearing
3 DR. GLASSER:
Thank you. I would just
4
like to start by saying thank you very much for the
5
opportunity to present.
6 [Slide]
7 I am going to be talking on the topic of
8
pseudophakic accommodation measurements. As
9
mentioned, my name is Adrian Glasser.
I am an
10
Associate Professor at the College of Optometry at
11
the University of Houston.
12 [Slide]
13 I am a scientist with research interest in
14
accommodation and presbyopia. I
have research
15
funding and I serve as a consultant to several
16
companies with interests in accommodation
17
restoration concepts. I am here
in my capacity as
18
an interested scientist and as a consultant to
19
industry.
20 My attendance at this meeting has been
21
sponsored by a company with interest in
22
accommodation restoration concepts.
I am not
23
talking about any specific devices so I have no
24
proprietary interests in anything I will be
25
presenting in this talk.
43
1 [Slide]
2 The purpose of my presentation is to
3
attempt to open a healthy, constructive and
4
informed dialogue between the FDA, researchers,
5
clinicians and companies with interests in
6
accommodation restoration concepts on the issues
7
and challenges of pseudophakic accommodation
8
measurement.
9 [Slide]
10 The presentation that I will make is
11
primarily directed at accommodative IOLs rather
12
than multifocal IOLs.
Accommodative intraocular
13
lenses are IOLs designed to provide uncorrected
14
vision over a continuous range of distances without
15
multifocality by producing an optical change in the
16
power of the eye through movement or through change
17
in shape of the optic. These are
IOLs designed to
18
provide dynamic accommodation.
Demonstrated proof
19
of efficacy is important for accommodative IOLs
20
and, perhaps even more so, if they are to be used
21
for the correction of presbyopia after clear lens
22
extraction.
23 [Slide]
24 Pseudophakic accommodation measurement is
25
important for patient informed consent, for patient
44
1
risk/benefit analysis, for clinical study design
2
and testing, for selection of clinical control
3
groups, for inclusion/exclusion criteria in
4
clinical trials, and in patient populations and for
5
product labeling following FDA approval.
6 [Slide]
7 I am going to ask more questions in this
8
presentation than I have answers for, and here are
9
some to start. What will the FDA
consider as the
10
gold standard for pseudophakic accommodation
11
measurement? How will the FDA
determine if the
12
benefits of an accommodative IOL outweigh the risks
13
of clear lens extraction? What
kind of
14
accommodation testing will the FDA require for
15
accommodative IOL clinical study designs? Will
16
these be subjective tests, objective tests or a
17
combination of both? What tests
or instrumentation
18
should researchers and clinical investigators
19
become familiar with for these clinical trials?
20
And, what kind of instruments will the FDA consider
21
as appropriate for objective accommodation
22
measurement, refraction to measure an optical
23
change in the eye versus, for example, A-scan
24
biometry to measure movements of an optic in the
25
eye?
45
1 [Slide]
2 I want to talk a little about subjective
3
testing of accommodation.
Distance corrected near
4
visual acuity with subjective push-up test and
5
negative lens-induced defocus have long been, and
6
remain, clinical standards for accommodation
7
testing. These and other
subjective tests are
8
easily implemented, are routinely used clinically.
9
They could readily by used in clinical trials and
10
they provide widely accepted indicators of
11
functional near vision, both for patients as well
12
as for clinicians. However,
these tests are not
13
quantitative measures of accommodative amplitude
14
and they do not unequivocally demonstrate an
15
accommodative change in optical power of the eye.
16
What reliance will the FDA place on these and other
17
subjective tests for future clinical trials of
18
accommodative IOLs?
19 [Slide]
20 I want to talk a little about producing an
21
accommodative response. To
measure accommodative
22
amplitude a full and maximum accommodative response
23
must be elicited from the subject or patient.
24
Accommodation can be stimulated with near or
25
proximal targets by inducing blur such as by
46
1
presenting minus lenses to induce defocus on a
2
distant letter chart, or with pilocarpine drops
3
directly applied to the eye.
Some individuals
4
accommodate poorly in some conditions to pure blur
5
fuse for example.
6
If no accommodation is
recorded, it does
7
not necessarily mean that the eye cannot
8
accommodate. It may simply mean
the subject has
9
chosen not to accommodate.
Pilocarpine drops on
10
the eye can be used to stimulate an involuntary
11
accommodative response. Will the
FDA consider
12
pharmacologically stimulated accommodation for
13
determining efficacy of accommodative IOLs?
14 [Slide]
15 I would like to talk a little about
16
objective measurement of accommodation.
Clinical
17
infrared autorefractors rely on analysis of
18
reflected light signals and often fail or are
19
inaccurate when light is reflected off high index
20
IOL materials.
21 Instruments often used to measure
22
accommodation objectively in research labs are no
23
longer commercially available.
New developing
24
instruments are lacking validation, are not
25
routinely available now, and their availability in
47
1
the future may be uncertain.
2 Standard clinical autorefractors, while
3
tested and validated on phakic eyes, have not been
4
tested and validated in pseudophakic eyes and may,
5
in fact, not measure accurately or may not measure
6
at all in pseudophakic eyes.
Lower accommodative
7
amplitudes expected of pseudophakic eyes will place
8
higher demands on the resolution of these
9
instruments.
10 [Slide]
11 Continuing with objective measurement of
12
accommodation, there is considerable uncertainty as
13
to the availability of instruments that are capable
14
of objective pseudophakic accommodation measure.
15 What objective instruments will the
FDA
16
accept or mandate for future clinical trials of
17
accommodative IOLs? Have these
instruments been
18
validation to accurately measure accommodation
19
either in pseudophakic or, in fact, in phakic eyes?
20
Will these instruments be able to reliably measure
21
pseudophakic eyes, and will these instruments be
22
generally available for placement at multiple
23
clinical sites?
24 [Slide]
25 I would like to talk a little about
48
1
comparison of performance with the standard or
2
monofocal IOL. Comparison with
the standard
3
non-accommodative, non-multifocal IOL using
4
accepted subjective clinical tests, such as
5
distance corrected near visual acuity, can provide
6
an indication of whether an IOL provides functional
7
near vision beyond that which would be provided by
8
the standard IOL.
9 Will the FDA accept subjective comparisons
10
of near visual performance with standard IOLs for
11
clinical trials of accommodative IOLs?
If so, what
12
level of improvement over the performance of a
13
standard IOL should be demonstrated?
How many
14
standard IOL control patients are required to
15
demonstrate efficacy of an accommodative IOL?
16 [Slide]
17 Finally, I will end by asking a few
18
general questions about what is required to
19
establish efficacy. For
accommodative IOLs is it
20
more important to establish the existence of
21
accommodation or to establish the amplitude of
22
accommodation?
23 If distance corrected patients can read at
24 near
after implantation of an accommodative IOL, is
25
this adequate to establish efficacy?
49
1 Many products are FDA approved without a
2
fully elucidated mechanism of action because they
3
work. Would this be adequate for
accommodative
4
IOLs?
5 How long a follow-up will be required to
6
demonstrate longevity of efficacy of accommodative
7
IOLs? And, will testing
standards for FDA approval
8
be different for accommodative IOLs versus for
9
multifocal IOLs? Thank you very
much.
10 DR. WEISS:
Thank you, Dr. Glasser. If
11
you would remain at the podium for a moment, are
12
there any questions from the panel while Dr.
13
Glasser is up at the podium? Dr.
Bradley?
14 DR. BRADLEY:
Thank you, Dr. Glasser for
15
that presentation. I think you
raise a very long
16
and challenging list of questions for the FDA and
17
it really would take too long to go through all of
18
them, but just a general question, you ask whether
19
pharmacologically induced accommodation would act
20
as a substitute for, let's call it, voluntary
21
accommodation. In your
experience, do you have any
22
reason to believe that it is an effective
23
substitute, or do you think there may be, for
24
example, a possibility that although one can induce
25
accommodation pharmacologically the patient could
50
1
not activate their accommodative mechanism
2
willfully? Is that a
possibility? Or, should we
3
be happy with pharmacologically induced
4
accommodation?
5 DR. GLASSER: I
wouldn't suggest that as a
6
substitute. I don't think that
it should be the
7
sole means of identifying whether an accommodative
8
IOL can produce an accommodative change. I do
9
think that it is an important addition perhaps to
10
the armament of tools that can be used to assess
11
the accommodative ability of an IOL.
12 Let me just add to that by saying that it
13
is well-known from the literature that myopes, for
14
example, have lower stimulus response functions
15
than emmetropes. So, there may
well be some
16
individuals in the patient populations who struggle
17
to elicit an accommodative response even if active
18
accommodation is truly there, and it might be
19
important to understand whether the lens inside the
20
eye is capable of accommodation.
I think the
21
pharmacological approach provides a useful tool in
22
that regard.
23 DR. BRADLEY:
Thank you.
24 DR. WEISS:
Seeing no other questions from
25
the panel, thank you very much, Dr. Glasser, for
51
1
your presentation. We are going
to then have Dr.
2
Lane.
3 DR. LANE:
Thank you, Dr. Weiss and
4
members of the panel for inviting me to share some
5
comments with you today about intraocular lenses
6
for presbyopia.
7 [Slide]
8 I am in private practice in the Twin
9
Cities. I am a clinical professor
at the
10
University of Minnesota in ophthalmology and among
11 a
number of different hats that I wear, I am a
12
clinical monitor for Alcon Surgical, for which I am
13 a
consultant, and I am here today representing them
14
and they have paid my expenses to be here.
15 [Slide]
16 As a means of introduction, I would like
17
to talk about presbyopia as not being a normal
18
state and, as I take out my reading glasses to try
19
and read some of my notes, that certainly becomes
20
very evident. It is a
progressive, degenerative
21
loss of the ability to accommodate and it is really
22
no different than an eye with any other refractive
23
error in that there is no structural damage done
24
but, clearly, it is not a normal eye.
25 The impact on the quality of life is
52
1
driving an increasing patient demand for spectacle-
2
and contact lens-free vision.
There are very high
3
expectations of the generally younger patient
4
population for this as is certainly evidenced by
5
the popularity of corneal refractive surgery.
6 [Slide]
7 As I look at things, there are really two
8
pathways in which I think the agency can proceed.
9
One is with the practice of medicine, that is to
10
say let the market forces play themselves out. The
11
second is to recommend formal clinical trials.
12 [Slide]
13 With regard to the practice of medicine,
14
the existing off-label practice medicine approach
15
of refractive lens exchange--which I am using
16
synonymously with clear lens extraction so it
17
depends whether you are coming from a cataract
18
point of view or you are coming from a refractive
19
surgeon point of view--is accepted in the
20
ophthalmic community and is continuing, and this is
21
continuing without the approved surgical options to
22
address safety and efficacy. As
we have already
23
heard, there have been no studies that have been
24
done looking at this in any long-term prospective
25
fashion, and despite inadequate information for
53
1
surgeon and patient informed consent.
2 [Slide]
3 Therefore, what is probably reasonable and
4
prudent is a refractive lens exchange clinical
5
trial. The development of a
reasonable, adequate
6
and well-controlled study focusing on safety and
7
efficacy assessment that will allow for the
8
appropriate informed consent is essential. Well,
9
"reasonable" is certainly a very nebulous term but
10
what we are really talking about here is being
11
practical. What we are talking
about is using the
12
already established safety record of modern
13
cataract surgery, and what we are talking about is
14
encouraging the use of existing regulatory
15
framework and guidance, wherever possible, from the
16
already existing body of information that we have
17
about cataract extraction and about refractive
18
surgery. We believe the study
should also address
19
the functional outcomes which are so important to
20
this group of patients and is really what is
21
driving the entire procedure.
22 [Slide]
23 The parameters to measure are very
24
well-known and I don't think we have to reinvent
25
the wheel here. Existing
regulatory guidance
54
1
already provides the sound basis for many study
2
measurement parameters: distance, intermediate and
3
near visual acuity and binocular defocus; stability
4
of refraction; contrast sensitivity; pupil size,
5
visual disturbances and adverse events; intraocular
6
lens observations and position; and certainly
7
quality of life.
8
[Slide]
9 As we look through the data, and we have
10
also done a very thorough literature search similar
11
to what was presented by Dr. Eydelman, we need to
12
mitigate the perceived risks with known outcomes
13
for modern cataract surgery.
This would include
14
things like endothelial cell loss.
Certainly, the
15
similarity, however, of this refractive posterior
16
chamber lens procedure to modern cataract surgery
17
eliminates, we feel, any need for ongoing
18
endothelial cell count measurements.
We have a
19
body of evidence in terms of modern clinical
20
cataract surgery done in a modern fashion.
21 But retinal detachment--again, the
22
numbers, depending on where you look, vary all over
23
the board. The numbers that we
looked at are
24
similar to those that were presented by Dr.
25
Eydelman and show that anywhere from 0.0-0.9
55
1
percent incidence of retinal detachment with modern
2
phacoemulsification techniques in the post-1980
3
era. This was modern cataract
literature that was
4
surveyed for retinal detachment risk factors.
5 [Slide]
6 The risk factors that we identified that
7
we believe should be proposed as potential
8
exclusion criteria are similar to those that were
9
discussed by Dr. Eydelman. We
too found that age
10
is a risk factor, especially less than 40; that
11
high myopia is a risk factor, especially greater
12
than 8 diopters; that axial length is a risk
13
factor, especially greater than 25 mm; and that any
14
history of peripheral retinal disease is a risk
15
factor.
16
Certainly, there are
surgically-related
17
risk factors. Posterior capsule
integrity is
18
critical. There is loss of
posterior capsule if
19
there is vitreous loss. If there
is a YAG laser
20
capsulotomy the incidence, as has been seen,
21
increases. However, with the use
of modern lens
22
removal techniques and new foldable intraocular
23
lenses, I think that many of these risks can be
24
minimized. Most of the studies
Dr. Eydelman
25
presented were from the early 1990s with larger
56
1
incisions, with PMA lenses, with different edge
2
designs and with different surgical techniques.
3
This is going to be a population of people that, by
4
and large, will have larger pupils; will have
5
softer lenses; will have many of the decrease in
6
risk factors that we now see in the cataract
7
population of patients that we are having to deal
8
with. So, we should be able to
perform safer
9
surgery.
10 [Slide]
11 The results of our retinal detachment
12
literature survey shows that the retinal detachment
13
rate in lens removal patients, when applying the
14
proposed exclusion criteria that were just
15
mentioned on the slide, was no different than that
16
occurring in the untreated population, which is
17
between 0.0 and 0.1 percent with up to 8 years of
18
follow-up.
19 [Slide]
20 With regard to control groups, and we
21
certainly understand that this is a concern that
22
has been voiced by the agency with regard to the
23
study, efficacy goals really should be reasonably
24
met without creating overly burdensome
25 requirements. We feel we must reasonably weight
57
1
the potential issues for the patients against the
2
value of the information to be gathered. Is it
3
reasonable? Is it fair? Is it practical for a
4
patient who comes in desiring refractive lens
5
exchange to be randomized to no treatment? I think
6
we must use the existing guidelines that we already
7
have in place for refractive procedures, for laser
8
procedures as we proceed and look at the choice of
9
control groups.
10 [Slide]
11 In summary, we have a number of proposals
12
that we would like the panel to consider. First,
13
we would like to minimize the study size and the
14
duration by employing the proposed exclusion
15
criteria derived from the retinal detachment
16
survey. Based on an incidence of
retinal
17
detachment of 1/1,000 using this exclusion
18
criteria, a clinical study that would be powered to
19
detect a difference would need to be an exceedingly
20
large sample size.
21 We would recommend that we apply the study
22
subject's own preoperative data to provide the best
23
method of control This provides
roughly the same
24
statistical power as using a non-operated control.
25
It is consistent with current guidance documents
58
1
and, importantly, it addresses the patient
2
considerations discussed previously.
3 [Slide]
4 We would ask to utilize the preoperative
5
endothelial cell minimum as an exclusion criteria
6
based on the FDA phakic IOL requirement in the
7
guidance that has already been given in that
8
respect. Finally, we would ask
to employ the
9
appropriate quality of life assessments, as an
10
example the RSVP survey.
11 [Slide]
12 In conclusion, I would like to take off my
13
Alcon hat here for a moment and put on my hat as a
14
teacher and as a practitioner and as a leader of a
15
number of ophthalmic organizations.
I recognize
16
that there are a number of various interests at
17
play here. From the patient's
standpoint, we want
18
to meet the demand of their increasing interest in
19
being totally spectacle and contact lens free.
20 We want to provide safe and effective
21
treatment that is based on real information and
22
true informed consent. As a
surgeon, I want to
23
provide the opportunity to deliver a service
24
desired by our patients which we can feel confident
25
about with regard to safety and efficacy.
59
1 As the FDA, I think you need and want to
2
fill a vacuum that presently exists and to set a
3
threshold of safety which we can live by and
4
industry, while certainly not in this for only
5
altruistic reasons, does want to produce products
6
that are safe and effective to fulfill patient
7
needs.
8 Finally, one that is not listed is
9
societal. Refractive lens
exchange allows the
10
potential for generations to come to reach Medicare
11
age with their lenses already removed, saving
12
government billions of dollars and, thus, becoming
13
the ultimate cataract preventative.
14 [Laughter]
15 All joking aside, I do see a real
16
opportunity here but unless reasonable and
17
practical considerations are employed, this
18
increasingly popular procedure will continue to be
19
performed outside the scope of the best interests
20
of the above parties. Thank you.
21 DR. WEISS:
Thank you, Dr. Lane. Do we
22
have any questions from the panel?
Dr. Grimmett?
23 DR. GRIMMETT:
Dr. Lane, thank you for
24
your presentation. I have a
question regarding
25
slide 7. I did a literature
review over the last
60
1
year or so when we discussed phakic IOLs and
2
endothelial cell loss and the long-term endothelial
3
cell loss rates we have been basing off old data
4
from Bill Bourne regarding procedures that we
5
really no longer perform. You
indicated on your
6
slide that we have known outcomes with modern
7
cataract surgery for endothelial cell loss rates
8
and I was wondering if you could direct me to the
9
literature reference or data regarding those known
10
outcomes.
11 DR. LANE: I am
sorry, Mike, I misspoke.
12
As you well know, there are no known--basically I
13
am using the numbers that have been used, and have
14
been used by the agency to go forward with a number
15
of the other studies that have gone forward and
16
approval processes for new intraocular foldable
17
lenses, and so on, using those data.
I guess from
18 a
historical perspective, if you will, the basis of
19
the endothelial cell counts from studies that have
20
been performed most recently with more modern
21
intraocular lenses, foldable intraocular lenses,
22
that have achieved approval by the agency seems to
23
be sufficient to allow approval of those particular
24
lenses. So, really I guess what
I am referring to
25
is data that has been presented from previous
61
1
applications, if you will, of foldable intraocular
2
lenses and the endothelial cell counts coming from
3
those and coming from oncoming studies that will be
4
looking at some new foldable lenses coming down the
5 line. So, from a
literature standpoint in terms of
6
going back and looking at the literature and is
7
there something out there that you have missed, the
8
answer is no.
9 DR. WEISS: Dr.
Mathers?
10 DR. MATHERS:
Thank you for your
11
presentation. I have a similar
question regarding
12
the rate of retinal detachment.
It would seem that
13
your slide suggesting that the rate of retinal
14
detachment in a select group after cataract surgery
15
is no greater than those that do not have cataract
16
surgery. But we heard this
morning of several very
17
large studies indicating that the retinal
18
detachment rate is considerably higher, and also is
19
highest in the youngest population for which we
20
seem to have the least amount of data.
Could you
21
explain this discrepancy?
22 DR. LANE: I
really don't see that there
23
is a discrepancy, Dr. Mathers, because the
24
literature that was discussed this morning included
25
the entire cohort. What we are
doing is separating
62
1
out the high risk factors. We
are separating out
2
the patients with high axial lengths.
We are
3
separating out the patients with high degrees of
4
myopia. We are separating out
patients with known
5
peripheral retinal disease. So,
the numbers that
6
were given that are higher are based on the entire
7
cohort that would include those while this group
8
includes only those that have those exclusion
9
criteria.
10 DR. MATHERS:
But do we have literature
11
that shows what the detachment rate in the younger
12
population with cataract surgery actually is?
13 DR. LANE: I
don't know the answer to
14
that, and I certainly don't think we know--I don't
15
know the answer to that.
16 DR. WEISS:
Just as a follow-up question
17
to that, if we are going to be suggesting that they
18
should be used in younger patients or used in
19
higher myopes, what would you suggest then be used
20
in those cases that we don't have the answer for
21
adverse event follow-up in terms of duration as
22
well as percentage?
23 DR. LANE: A
very good question. I don't
24
obviously have the answer to that either, but I
25
think that in the same way in which Dr. Eydelman
63
1
suggested that the introduction of any presbyopic
2
lens be performed in a cataract population first,
3
the next logical step to me would be to perform it
4
in a group that included certain exclusion criteria
5
that we are talking about. If
that trial proves to
6
be successful, as it would have to be if it was
7
going on to the next step, then the next step would
8
be to try some of the higher risk population and
9
perform adequate studies to be able to show that.
10 DR. WEISS:
Just a follow-up question, if
11
you were putting this study together what would you
12
want in terms of range of refractive error? It
13
sounds like you would be suggesting that the
14
refractive errors that are most in demand to have
15
this done, namely the very high myopes, be
16
eliminated from an initial study and the younger
17
patients be eliminated from an initial study. Or,
18
am I misreading what you are saying?
19
DR. LANE: No, you are not misreading what
20 I
am saying. I think that, you know,
based on the
21
literature search that we did looking at the
22
exclusion criteria that are present, that is the
23
group of patients that I think should be targeted.
24
While, yes, the high myopes would certainly benefit
25
potentially from this kind of technology and may be
64
1
the ones who would really sort of gather at your
2
doorstep to do this in greatest numbers, for the
3
time being certainly all of the literature suggests
4
that those patients are at higher risk.
So, I
5
think, again, that may be a study that needs to be
6
done in a better fashion using more modern
7
techniques but I think we have to get there
8
probably in a step-wise fashion rather than trying
9
to do it.
10 I wouldn't necessarily agree that the
11
majority of patients who would want to have this
12
are necessarily the high myopes.
There is a whole
13
group of presbyopic patients out there who would
14
want to have this for presbyopic reasons. While
15
that certainly is an important group, it is
16
certainly not the only group and may not even be
17
the largest group.
18 DR. WEISS: Dr.
Stark, did you have a
19
question?
20 DR. STARK: You
did show a reference on
21
slide 9, Solomon, indicating that the retinal
22
detachment risk was 0.1 percent.
It went by so
23
fast I didn't get it--
24 DR. LANE: That
is in the untreated
25
population. That is very similar
to the
65
1
information that Dr. Eydelman presented. It is
2
essentially a control group, if you will.
3 DR. STARK: Oh,
okay. Good.
4 DR. WEISS:
Seeing no other questions from
5
the panel, thank you very much, Dr. Lane, for your
6
presentation. Dr. Randall Olson
has a letter that
7
Sally Thornton will be reading as part of the open
8
public hearing presenters.
9 MS. THORNTON:
This is a letter from Dr.
10
Randall Olson, who is the John A. Moran
11
Presidential Professor and Chair of the Department
12
of Ophthalmology and Visual Scientists, and
13
Director of the John A. Moray Eye Center at the
14
University of Utah Health Science Center:
15 I would like to comment on the use of
16
intraocular lenses for correction of presbyopia
17
after clear lens extraction, a topic that is to e
18
discussed by the Ophthalmic Devices Panel of the
19
Medical Devices Advisory Committee on Friday, March
20
5, 2004. We have performed about
100 "clear"
21
lensectomy procedures in presbyopes over the past
22
two years. The term
"clear" lensectomy is a
23
misnomer for us. In our patient
population, it is
24
rare for a presbyopic patient not to have some
25
level of lens opacification, even though it may not
66
1
be significantly decreasing their Snellen visual
2
acuity. In a study, done by
Waltz, Wallace in
3
Ophthalmic Practice, 2001, of over 200 refractive
4
lensectomy patients, the average age at surgery was
5
53 years, our average is even older.
We feel that
6
we are doing these patients a disservice to perform
7
corneal surgery, such as LASIK, when cataract
8
surgery due to further lens opacification may be
9
just around the corner. The
precision of the
10
refractive component of cataract surgery drops
11
precipitously for post corneal refractive patients,
12
and it is precisely this group that demands
13
refractive precision.
14 For the patient, clinical studies have
15
shown a high rate of patient satisfaction with
16
refractive lensectomy. They
perceive being
17
"spectacle free" as an improvement in their quality
18
of life. With the present levels
of refractive
19
precision, the acceptance rate is as good as, or
20
better than, LASIK.
21 The only concern for refractive lensectomy
22
that could conceivably be greater than cataract
23
complications is the possibility of an increased
24
rate of retinal detachment following surgery in
25
high myopes. The retinal
detachment risk is not
67
1
germane for emmetropes or hyperopes.
We have
2
published several studies in this area, Powell,
3
Olson Journal of Cataract and Refractive Surgery,
4
1995, Olsen and Olson in the Journal of Cataract
5
and Refractive Surgery, 1995, and Olsen and Olson
6
in the Journal of Cataract and Refractive Surgery,
7
2000, showing a decrease in the rate of retinal
8
detachment as surgical techniques and equipment
9
have improved. For high myopes,
the risk probably
10
can be reduced by careful prescreening and the use
11
of a phaco technique that maintains the depth of
12
the anterior chamber during surgery.
It should
13
also be noted that the lens is less dense and more
14
easily removed in refractive lensectomy patients
15
than cataract patients. This
reduces surgical
16
complications for this group.
17 In spite of the issue of retinal
18
detachment in high myopes, which has been
19
investigated in multiple studies, a prospective
20
study of "clear" lensectomy does not seem
21
warranted, in that our cataract database is already
22
so large and so inclusive. In
additional, to truly
23
study "clear" lensectomy in presbyopic patients
24
would be extremely difficult since few of these
25
patients have clear lenses.
68
1 Signed, Randall J. Olson, M.D. Thank you.
2 DR. WEISS:
Thank you, Sally. That will
3
conclude the open public hearing session. We will
4
break for 15 minutes before beginning the panel
5
deliberations.
6 [Brief recess]
7 Panel Deliberations
8 DR. WEISS: We
are now going to open the
9
panel deliberations session and I will ask, Dr.
10
Eydelman, if you could come to the podium and
11
perhaps we could use the questions as a guidance.
12
Actually, perhaps Dr. Blustein could come forward
13
as well so that if there are any questions for the
14
FDA from their panel presentation we could have the
15
panel ask those at this time. Do
any of the panel
16
members have questions for FDA?
Dr. Ho?
17 DR. HO:
Malvina, just a question on the
18
FDA grid for PC IOLs, what is that data derived
19
from?
20 DR. EYDELMAN:
One second and I will show
21
you, I am just going to put the slide up.
22 [Slide]
23 This was a composite of all the PMA data
24 that was performed. As you see, the total N was
25
5,906 eyes. This particular grid
encompasses all
69
1
surgeries from '87 to '96.
2 DR. HO: So, it
is a mixed bag with
3
respect to the way the cataracts were removed I
4
suspect.
5 DR. EYDELMAN:
Correct. We actually
6
looked at this specific question two days ago
7
because we were considering it under ISO. We have
8
unofficially re-looked at what these numbers would
9
be if we just moved it forward.
10 MR. CALOGERO:
At the last ISO meeting
11
this week we looked at updating the grid and we did
12
some early, preliminary work.
Unfortunately, I
13
don't have the grid values. They
changed somewhat
14
but what we did, we truncated off the oldest PMAs
15
and now, if you look at the data from 1994 out to
16
2003, there are minor changes in these rates but
17
the retinal detachment rate goes down somewhat.
18 DR. EYDELMAN:
The only number that was
19
significantly different was the CME.
It went from
20 3
percent to 1.5 percent. But since that
was
21
unofficial, sort of our little draft, we didn't put
22
that up. This is the official
FDA grid that the
23
companies have been comparing their IOLs to.
24 DR. HO: Thank
you.
25 DR. WEISS: Dr.
Grimmett?
70
1 DR. GRIMMETT:
A question in follow-up,
2
Dr. Eydelman, did the hyphema rate go down?
3 DR. EYDELMAN:
Slightly.
4 GRIMMETT:
Slightly?
5 DR. EYDELMAN:
Slightly. For the purposes
6
of ISO, we were looking if it would change at all
7
our sample size for determination and it didn't.
8 DR. GRIMMETT:
That is surprising to me
9
because, at least in my clinical practice, it is
10
just not common to see hyphema after modern phaco
11
surgery. So, I am just surprised
by that.
12 DR. EYDELMAN:
I think it was 1.5. I
13
don't want to quote, I don't have the numbers but
14
it was over 1 percent. Again,
cumulative is
15
defined as occurring any time between surgery to
16
one year. It is just additive.
17 DR. WEISS: Mr.
McCarley?
18 MR. MCCARLEY:
Yes, Rick McCarley. I have
19
three quick questions.
Hopefully, they will have
20
quick answers. Are we limiting
the discussion
21
today to multifocal lenses and accommodative IOLs
22
or are we also talking about standard monofocal
23
IOLs where you would use monovision, for instance?
24
In other words, any IOL that is placed in the eye
25
to correct the patient who can no longer
71
1
accommodate?
2 DR. EYDELMAN:
The discussion was intended
3
to be limited to the correction where the subjects
4
have both distance and near VA for correction of
5
presbyopia.
6 MR. MCCARLEY:
So, not for monofocal IOLs?
7 DR. EYDELMAN:
Well, it could include
8
accommodative.
9 MR. MCCARLEY:
That is not accommodative?
10 DR. EYDELMAN:
Correct. It is for those
11
IOLs that simultaneously provide distance and near
12
VA corrections.
13 MR. MCCARLEY:
Okay. The second question
14
is what is the FDA's current labeling for, for
15
instance, accommodative IOL or the multifocal IOL
16
related to the age range that they suggest? In
17
other words, my understanding is it used to be 60
18
years and older but that was changed later on to be
19
adults not less than 18 or not less than 21. Is
20
that correct?
21 DR. EYDELMAN:
Currently all IOL sponsors
22
may require an indication for the adult population,
23
but that is for IOLs status post cataract
24
extraction, correct.
25 MR. MCCARLEY:
My final question is the
72
1
FDA knows that this clear lens extraction has been
2
going on for a while and knows that it is
3
increasing in popularity. Has
the FDA, in the
4
interest of public health, done anything to inform
5
doctors or patients now, working with maybe the AAO
6
or the SCRS, to let them know what we know now so
7
that they will be better informed for what we know
8
is going on? In fact, what do
you have planned
9
between now and when any study might be completed?
10 DR. EYDELMAN:
Well, as I mentioned, it
11
has only been done as off-label and, as such, it
12
has been quite an issue.
Off-label means we do not
13
have an approved indication with safety and
14
efficacy data that we can share.
15 MR. MCCARLEY:
So, you recognize there is
16 a
potential public impact but the FDA doesn't feel
17
they can do anything right now to notify the
18
doctors or the patients?
19 DR. WEISS: Do
you want to comment on
20
that, Ralph?
21 DR. ROSENTHAL:
We are a regulatory agency
22
that regulates the medical device industry and it
23
is not our responsibility to inform the public
24
about issues regarding off-label use unless we feel
25
there is a significant public health issue.
73
1
MR. MCCARLEY: I thought that was how Dr.
2
Eydelman's presentation started off, that this is a
3
significant, major public health issue.
4 DR. EYDELMAN:
No, my presentation started
5
off that if CLE for correction of presbyopia
6
becomes widely used it can have a significant
7
health impact. As an aside, I
said that CLE has
8
been performed as off-label use, mostly for high
9
refractive errors. Those two are
two distinct
10
ideas.
11
DR. WEISS: I think also some companies
12
would like to get this on-label so I don't believe
13
it is just being driven by FDA.
Dr. Mathers?
14 DR. MATHERS:
Is there any data indicating
15
that the movement of an accommodative IOL would
16
have any bearing on, say, position of the vitreous
17
space or affect retinal detachment, uveitis or
18
endothelial cell loss? In other
words, there
19
appears to be no downside to an accommodative IOL
20
that changes its position but there might be
21
compared to another kind of straight IOL. Do you
22
have any data on that?
23 DR. EYDELMAN:
No, we don't. We only have
24
one, as you know, IOL currently approved so we have
25
very limited information on that issue.
74
1 DR. WEISS: Any
other questions from the
2
panel? Seeing no other
questions, we can then
3
address the first question that the FDA is asking.
4 1 A), do you recommend a control
5
population for studies of clear lens extraction in
6
the correction of presbyopia, or do you believe
7
that the study subject's own preoperative data is
8
sufficient for comparison?
9 This is basically going to be a yes or no,
10
and I want to poll each of the panel members if
11
they want a control population or is the study
12
subject's own preoperative data sufficient? We
13
will start with Dr. Maguire.
Would you like a
14
control population, Dr. Maguire, or is preoperative
15
data from the patient enough?
16 DR. MAGUIRE: I
am going to pass right
17
now.
18 DR. WEISS: We
have an abstention. Dr.
19 Stark?
20 DR. STARK:
Well, I think it would be
21
difficult to randomize patients, if they wanted
22
this procedure, to no treatment or treatment. So,
23 I
think we could get enough information on
24
complications if we had adequate long-term
25
follow-up. My primary concern
would be the retinal
75
1
detachment rate even in young people who are not
2
myopic. So, I think we could get
this from
3
historical control or age-matched populations. So,
4 I
don't think a randomized, controlled study is
5
necessary in this.
6 DR. WEISS: I
am just going to step back
7
for this question, for part A), it is not actually
8
the type of control population but whether or not
9
you want a control population.
From what I
10
understand from what you are saying, you do want a
11
control population but not something so onerous
12
but, still, you would like a control population.
13
Is that correct?
14 DR. STARK:
Yes.
15 DR. WEISS: Dr.
Brown?
16 DR. BROWN:
Yes, I do feel strongly about
17
that. I would like there to be a
control
18
population, particularly if we include high myopes
19
in any of thee studies.
20 DR. WEISS: So,
you would like a control
21
population as well. Dr. McMahon?
22 DR. MCMAHON: A
question--we are jumping
23
right into controls but are we talking from a
24
perspective of efficacy or safety, or both?
25 DR. EYDELMAN:
We are talking with respect
76
1
to study design.
2 DR. BRUCKER:
Can I raise a question?
3 DR. WEISS:
Actually, what I would like to
4
do is not have a discussion now but sort of get a
5
feeling for where people are at.
Then, once we get
6
involved in the type of control population we will
7
break it up into discussion.
8 DR. BRUCKER:
Could I still ask the
9
question because it is applicable to what you are
10
asking.
11 DR. WEISS:
Okay, Dr. Brucker.
12 DR. BRUCKER:
Clear lens extraction is a
13
surgical procedure--
14 DR. WEISS:
Yes.
15 DR. BRUCKER:
That surgical procedure can
16
be done by any physician at any time, period.
17 DR. WEISS: A
hundred percent correct.
18 DR. BRUCKER:
The risks and complications
19
that we are talking about have to do with clear
20
lens extraction. It has nothing
to do with the
21
insertion of an IOL. So, the
question that you are
22
posing seems to be a question that can't be taken
23
out of that context. The
insertion of an
24
intraocular lens is not assumed, from my
25
understanding, to be the cause of the complication.
77
1
Therefore, the use of a surgical procedure called
2
clear lens extraction should have nothing to do, in
3
my opinion, with whether you put in monovision,
4
presbyopic vision or anything else; it is clear
5
lens extraction. Perhaps we
should have a little
6
bit of discussion about the issue of clear lens
7
extraction before you start talking about
8
intraocular lenses.
9 DR. WEISS: I
think technically what you
10
are saying from a purist standpoint is correct,
11
however, when IOLs get evaluated they get evaluated
12
in terms of hyphema and retinal detachment rate
13
and, from what you are saying, they shouldn't be
14
evaluated in that way either because the IOL is not
15
causing the RD or the hyphema but, yet, it is
16
included in the surgical procedure and when the
17
patient is going in for that surgical procedure you
18
can't separate out for them that, oh well, this is
19
the part that caused it and this part didn't cause
20
it.
21 So, for the purpose of this discussion,
22
although your points are well taken and FDA can
23
correct me, I think it doesn't really apply. We
24
still have to put it all together because when a
25
patient is looking at it, who is 45 years old, who
78
1
is a minus 15, whether they are getting the RD 7
2
years down the line from the IOL or they are
3
getting it from the surgical procedure they are
4
still going to end up with an RD and that is the
5
information they need. Agency,
would you agree?
6 DR. EYDELMAN:
You are absolutely correct
7
because we are talking about approval of a
8
particular IOL for a specific indication and that
9
indication would incorporate a clear lens
10
extraction which would precede the implantation.
11
So, it is looked at as a package deal.
12 DR. BRUCKER:
Yes, but you presented
13
Ripandelli's work and many of the eyes in
14
Ripandelli's work didn't have IOLs.
They had clear
15
lens extraction and they had retinal detachments.
16
It is the retinal detachment coming from the clear
17
lens extraction that really is the subject of
18
discussion.
19 DR. WEISS: Dr.
Brucker, as I said, I
20
think from a logical technology standpoint, you are
21
right but it doesn't apply to what the agency wants
22
at this point. Dr. Bressler?
23 DR. BRESSLER:
I think you do need a
24
control, and it will be more interesting discussing
25
what that will be on the second round.
79
1 DR. WEISS: Dr.
Smith?
2
DR. SMITH: I agree, you need a control
3
both for safety and efficacy.
4 DR. WEISS: Dr.
Ho?
5 DR. HO: The
clinician scientist in me
6
wants an active control, however, I recognize the
7
difficulty of executing a trial in which someone is
8
seeking a refractive procedure and would be
9
randomized--
10 DR. WEISS:
Just to reiterate, we don't
11
have to commit--
12 DR. HO: I
would be okay with historical
13
age and refractive-matched controls.
14 DR. WEISS: All
I want from anyone right
15
at this moment is do you want a control or you
16
don't want a control. I am going
to keep it nice
17
and simple. It won't stay simple
for long so enjoy
18
it while you have it. Dr.
Mathers?
19 DR. MATHERS:
By patients on control, are
20
you supposing that you do the surgery in one eye
21
and not on the other?
22 DR. WEISS:
Well, any type of control you
23 want.
It is just question 1 (A, do you want a
24
control or you don't want a control?
You are going
25
to tell us afterwards what sort of control you
80
1
want.
2
DR. MATHERS: I want a control.
3 DR. WEISS: You
want a control. Dr.
4
Grimmett?
5 DR. GRIMMETT:
Yes.
6 DR. WEISS: Dr.
Grimmett wants a control.
7
Dr. McMahon?
8 DR. MCMAHON: Yes.
9 DR. WEISS: Dr.
Bradley?
10 DR. BRADLEY: I
am not sure.
11 DR. WEISS:
Another abstention. Dr.
12
Ferris?
13 DR. FERRIS: We
have to have some sort of
14
comparison group so the answer of who wants some
15
sort of comparison group is simple, so I want a
16
comparison group.
17 DR. WEISS:
Thank you. Dr. Brucker just
18
nodded in the affirmative. Mr.
McCarley, you can
19
voice your opinion, of course.
20 MR. MCCARLEY:
I was just thinking of the
21
same patient control.
22 DR. WEISS:
Okay, and Dr. Maguire, did you
23
want to voice an opinion at this point?
24 DR. MAGUIRE:
Well, yes, because we
25
haven't really established what we are talking
81
1
about so I don't want to say no.
2 [Laughter]
3 DR. WEISS: I
take that as a continuation
4
of an abstention. I am hearing
somewhat of a
5
consensus on 1 A), that most of the panel would
6
like to have a control population.
So, now we get
7
into 1 B), which is on the screen, what type of
8
control population would you like.
We have the
9
historical and the active, or if you can come up
10
with anything else. I don't
believe the FDA was
11
emphasizing doing a randomized study.
I don't
12
really think anyone is talking about that, but if
13
that is what you want to do you can certainly
14
suggest it. In the list of
controls under
15
historical under 1 B) there are subjects--well, you
16
can read them yourself. There
are four different
17
types of historical controls.
There is one type of
18 active
control, and then if there is anything else
19
that you would like. Dr.
Rosenthal?
20 DR. ROSENTHAL:
The active control would
21
be a group of patients who had no surgery. So, in
22
fact--
23 DR. WEISS: It
could be randomized.
24 DR. ROSENTHAL:
--you could randomize or
25
you could just collect a group of patients.
82
1 DR. WEISS:
Then the randomization is
2
actually another level of specificity.
You could
3
have an active control of another group of, let's
4
say, age- and gender- matched subjects, and how you
5
wanted to include them in the study, actually, the
6
FDA has not even asked us. So,
they haven't even
7
asked us for that level of detail.
8 Let's start with Dr. Maguire, if you
9
wanted to voice your opinion on this.
10 DR. MAGUIRE:
Yes, I think active control
11
subjects with no previous ocular surgery and not
12
planning on having any either for presbyopia would
13
be reasonable.
14 DR. STARK:
Agreed.
15 DR. MAGUIRE:
Because we have no
16
information on retinal detachment surgery in young
17
people, or certainly not adequate information, and
18
we would like to have more information on
19
endothelial cell loss based on Dr. Lane's answer to
20
Dr. Grimmett's question, so absolutely.
21 DR. WEISS: So,
you would like an active
22
control of subjects with no previous ocular
23
surgery. Dr. Stark agreed with
that. Dr. Brown?
24 DR. BROWN:
Yes, an active case control
25
study that is matched on criteria that we would set
83
1
out in terms of refractive error and age, yes.
2 DR. WEISS: So,
you would also like an
3
active control. Dr. Bressler?
4 DR. BRESSLER:
I would like to discuss for
5 a
minute a couple of considerations for why a
6
randomized control might be beneficial for getting
7
the answer and then we can get back to would those
8
people actually enroll.
9 We may see some visual acuity loss in a
10
few of these people that have this.
In the few
11
studies that were done, granted in the high myopes
12
with clear lens extraction they did have one or two
13
people that are 40 losing a line of vision by six
14
months, for example, in their best corrected visual
15
acuity. Now, that could be to
the detriment of
16
this if you didn't have a control group because you
17
would say, well, they started at 20/16 and they
18
dropped to 20/25, or something.
However, it could
19
be that your control group developed some cataract
20
along the way. We are going to
have 50 year-olds
21
with presbyopic symptoms, or whatever, and they may
22
drop to 20/25 just as often. So,
you never would
23
have known that you weren't harming their vision,
24
for example, more than if you left it alone if you
25
didn't have a control group for that.
84
1 In addition, if you are going to look at
2
quality of life outcomes, for example, whatever
3
answers or change in the quality of life you get in
4
someone over time, you just won't know if that is
5
just due to the person having the surgery done and
6
being happy with their life or if it is due to
7
other factors that you would only get from a
8
control group.
9 So, I am all for an active control and I
10
think it needs to be considered as actually a
11
randomized trial to be able to answer the important
12
safety issue, which will be visual acuity besides
13
the retinal detachment, which is much rarer and you
14
may not be able to detect those changes, and any
15
quality of life studies that might be considered
16
down the line.
17 DR. WEISS: I
would ask you if this could
18
not be a randomized study because it was deemed
19
that it would be too burdensome or the study
20
wouldn't be able to accrue the patients because of
21 that criteria, would you still want an active
22
control? Would that still be
something that you
23
would want?
24 DR. BRESSLER:
If you couldn't have it,
25
then yes, but you might not be able to answer these
85
1
questions if you see that the visual acuity has
2
declined. So, I just don't want
to have the
3
industry paint themselves into a corner. That is
4
the whole advantage of doing this ahead of time.
5 DR. WEISS: Dr.
Eydelman?
6 DR. EYDELMAN:
Along the lines of what Dr.
7
Bressler just mentioned, the panel certainly can
8
consider whether they wanted two different controls
9
for safety and efficacy outcomes.
If that is the
10
case, that just puts a little further question into
11
question 1 B).
12 DR. BRESSLER:
I am not separating it
13
because safety assessment depends on what the
14
efficacy is as well. You are
willing to take big
15
safety risks for one sort of efficacy and less
16
safety risks for another.
17 DR. EYDELMAN:
Right, but determination of
18
safety and efficacy with an active control is going
19
to require greatly different sample sizes. Just
20
keep that in mind.
21 DR. WEISS: Dr.
Smith?
22 DR. SMITH: I
would prefer to have an
23
active control while recognizing these concerns
24
that several have voiced regarding the feasibility
25
of doing such a study, and I am open to discussing
86
1
ways to do that other than randomization but I do
2
believe in active controls. It
is critical to
3 obtaining
safety data in this age group for which
4
we do not have good data.
5 DR. WEISS:
Just to remind panel members,
6
we welcome dissent. We don't
need unanimity on
7
this. This is really to guide
the agency as far as
8
the panel's sentiments so we don't have to have a
9
continual roll here if you want to go in another
10
direction. Dr. Ho?
11 DR. HO: As I
was saying before, as a
12
scientist I think that I would love to have an
13 active
control. I think it would be very
difficult
14
to execute that study. I think
Neil's concern and
15
point is a good one, however, the duration of the
16
study will likely not be long enough so that maybe
17
those 1/40 patients that drop a line might not drop
18 a
line in the first few years.
19 DR. WEISS:
Would you be able to get a
20
little closer to the mike?
21 DR. HO:
Sure. Therefore, I would be open
22
to a historical control but it would have to be an
23
age-matched and refractive error-matched control.
24 DR. WEISS:
Would that be difficult to do,
25
Dr. Eydelman? I just saw a
change in your
87
1 expression, not for the
positive.
2 DR. EYDELMAN:
Well, that would imply that
3
each sponsor, depending on the inclusion/exclusion
4
criteria, would have to go through the literature
5
and try to see if they can pull--most of the
6
articles don't have raw data so you would have to
7
try to identify articles that have exactly the same
8
age criteria as you wish to enroll.
It gets a
9
little tricky. We have done it
for glaucoma
10
devices and the sponsors found it quite difficult.
11 DR. WEISS: Dr.
Bressler?
12 DR. BRESSLER:
I just wanted to add to
13
Allen's comment that in the small series we had
14
from Dick and colleagues, that was only a six-month
15
follow-up and they had 3/50--and I know these are
16
broad confidence intervals but that was six percent
17
losing one line. So, you might
get those answers
18
even with just a year follow-up or safety beyond
19
two years.
20 DR. WEISS: Dr.
Ho?
21 DR. HO: That
was also a group that was
22
highly myopic that might be more susceptible than
23
the general group you are speaking to here who
24
would like to have presbyopic surgery.
25 DR. WEISS: So,
Dr. Ho, you still would
88
1
prefer to have a historical?
2 DR. HO: If
that data can be derived, yes,
3
because I think consideration of an active
4 control--although burdensome and I would love
it
5
but I think it would be difficult to execute that
6
trial.
7 DR. WEISS:
Would I be able to ask you to
8
sort of isolate one of the four listed here as far
9
as what type of historical control?
No, I would
10
not be able to? Okay, well, I
can ask. Dr.
11
Mathers?
12 DR. MATHERS: I
don't think it would be
13
that difficult to have an active control because
14
you are not really doing too much for these people
15
if they haven't had surgery. You
are just
16
following them and you are doing some tests on
17
them. But I think that you would
have to stratify
18
them to answer some of the questions.
You would
19
have to stratify them by axial length, refractive
20
error, endothelial count and age.
If you did that,
21
you could answer these questions and I do think it
22
is extremely important to answer these questions.
23
We are talking about really major health issues
24
here that affect millions, if not billions, of
25
people and, clearly, the private community or the
89
1
academic community have all completely failed to
2 look at this fundamental issue and maybe we
have an
3
opportunity to help them. We
haven't answered
4
these questions yet. Obviously,
the literature
5
shows we have not.
6 DR. WEISS: Dr.
Grimmett?
7 DR. GRIMMETT:
For effectiveness issues I
8
would be in favor of an active control.
Certainly
9
for quality of life issues it would be very nice to
10
compare patients who have not had surgery with time
11
to see how their quality of life compares to those
12
who have had the surgery.
13 Dr. Eydelman read my mind as far as
14
separating safety and effectiveness.
I could go
15
with a historical control for safety issues,
16
perhaps patients who have had cataract surgery with
17
IOLs.
18 DR. WEISS: I
have just been informed
19
that, unlike many panel meetings, my opinion is
20
actually wanted on this one even though I am
21
chairing this. So, I think I
would like an active
22
control as well because of the frustration I think
23
for a sponsor as well as the panel often when the
24
PMA is presented and we don't have the information
25
to assess--let's say, the risk or whatever--and the
90
1
best way to do that is to compare it to an active
2
control. Although randomization
would be
3
wonderful, I think it would be too onerous on the
4
sponsors so I wouldn't be supporting that. Dr.
5 McMahon?
6 DR. MCMAHON: I
have a few comments on
7
this issue. I agree with Dr.
Bressler that a
8
randomized trial with an active randomized control
9
group would be ideal, but I also agree with you
10
that it would be a bit onerous to maintain an
11
active control group for a period of three or four
12
years. Keep in mind, this is
equivalent to a
13
refractive surgery population and keeping track of
14
the patients is hard enough, let alone controls who
15
might also be interested in this procedure. If you
16
are going to hold them off for several years I
17
think it would be very difficult to manage this.
18 With regard to active controls, I think
19
there are other mechanisms that can be played and I
20
think it can be done in a variety of interesting
21
ways. For the less common but
more devastating
22
complications like retinal detachment I can see a
23
design where you have a prospective case control
24
kind of circumstance where you have a lot of active
25
controls who are not interested in the procedure
91
1
and a lesser number of actually operated patients.
2
But for things like efficacy
you are going
3
to want more of a matched controlled set of
4
patients in that circumstance.
So, I think an
5
active control group is the thing to do. I think
6
randomization is likely not to be manageable but
7
there are other options I think that can be looked
8
at.
9 DR. WEISS: Dr.
Bradley?
10 DR. BRADLEY:
Yes, I have several
11
comments. I think taking Dr.
Brucker's comment
12
earlier to heart in that potentially the greatest
13
risk here is the surgical procedure not the lens
14
being inserted into the eye, one might not imagine
15
dramatically different risks associated with
16
different lenses. So, we may,
therefore, be able
17 to
employ historical literature controls for risk,
18
particularly in the age group that has already
19
undergone this particular surgery, which is
20
obviously the 50-plus age group and they have
21
obviously been having surgery for cataracts. So,
22
this may be effectively evaluated using historical
23
controls in the older group.
That is certainly not
24
the case if the lenses are going to be inserted in
25
younger eyes. I think in that
case an active
92
1
control for risk is required.
2 Regarding controls for efficacy, clearly,
3
if we are going to be reviewing novel multifocal or
4
novel accommodative IOLs, I think efficacy will
5
require an active control. So,
again, I am sort of
6
dividing it between safety and efficacy. I think
7
efficacy will require active controls even in the
8
older group but safety may not.
9 DR. WEISS: Dr.
Ferris?
10 DR. FERRIS:
Some people may be shocked to
11
hear me say this. In fact, I am
shocking myself to
12
say this, but I agree with Malvina that we need to
13
look at this separately for safety and efficacy and
14 I
am saying that in part not, as Allen says,
15
because of what is scientifically best but what is
16
reasonable to do. From my
perspective the
17
appropriate control group, particularly for these
18
younger people that are considering to have this
19
done for presbyopia, is the unoperated group. The
20
choice is wearing glasses and the risk of wearing
21
glasses is pretty low.
22 So, the underlying rates that have been
23
presented today for retinal detachment and
24 endothelial cell loss are probably the appropriate
25
rates to look at. They are so
low that if you
93
1
tried to figure out the sample size that would be
2
necessary to have reasonable confidence intervals
3
around those rates, it is sort of an impossible
4
study. So, from one perspective
I would think that
5
you would take the point of view that for safety
6
the rate is almost zero or very low.
So, what you
7
want to know is what is the rate if you do this
8
procedure and I would bundle the whole procedure as
9
you were mentioning, the surgery plus the lens,
10
plus everything. So, from the
safety side I think
11
that is the way that I would do it so I am saying I
12
guess historical controls.
13 Efficacy is a different issue I think
14
because now you can have an appropriate sample size
15
and, as Neil pointed out, whatever it was, 6
16
percent loss or 3 percent one line loss is what you
17
would find if you just repeated the visual acuity
18
the same day. There is a certain
5-letter change
19
in our experience. So, usually I
say results are
20
always improved by omitting the control group. In
21
this case they are worsened by omitting the control
22
group. So, i would think from
the company's point
23
of view they probably want an active control group
24
and that control group may be several things. One,
25
as mentioned here, their preexisting state, which I
94
1
think is a very important control group and,
2
secondly, maybe a comparable group, particularly if
3
you are going to look at changes over time and
4
quality of life. I also agree
that doing a
5
randomization trial is virtually impossible. On
6
the other hand, uncontrolled confounding is going
7
to be an impossible issue to deal with when you
8 don't
have a randomization comparison. So, it
is
9
sort of skewed either way.
10 DR. WEISS: I
think both Dr. Bradley and
11
yourself bring up a very good point.
Just to sort
12
of elucidate it a little bit further, if you are
13
going to be doing a historical control for safety,
14
could you just clarify which one of those groups
15
you would both be using?
16 DR. FERRIS:
From my view, it is the
17
untreated group, and the only caveat there is this
18
untreated group is potentially treated.
As was
19
pointed out in discussions, eventually a large
20
proportion of these people are going to have
21
cataract surgery in their lifetime.
The other
22
thing that we will bring up later but what I think
23
is very important is it is not the four-year risk
24
of retinal detachment, it is the 25-year risk of
25
retinal detachment.
95
1 DR. WEISS: So,
you would like a
2
historical control of subjects with no previous
3
ocular surgery for safety but for efficacy have an
4
active control. Dr. Bradley?
5 DR. BRADLEY: I
think my views on the
6
safety control group would be, again, the untreated
7
group.
8 DR. WEISS:
Basically you are in agreement
9
with Dr. Ferris.
10 DR. BRADLEY:
Yes, the one qualifier is
11
that there is a presumption that the literature
12
provides adequate data to support a historical
13
control, and my reading of the literature and the
14
presentations today lead me to believe that within
15
the cataract age group we have adequate data to
16
have historical literature-based controls but we
17
don't in the younger age group.
18 Again, the question is where is the
19
cut-off and I think that is perhaps for the FDA to
20
determine. Where does the
literature adequately
21
provide this control?
22
DR. WEISS: Dr. Eydelman?
23 DR. EYDELMAN:
If you are choosing to talk
24
about appropriate historical control being subjects
25
with no previous ocular surgery, then we have
96
1
adequate data in the literature for all ages.
2 DR. WEISS: Dr.
Ferris?
3 DR. FERRIS:
Well, just one other comment.
4
The one place where perhaps an active control group
5
would be useful for evaluating complications might
6
be in the high myopes. A side
issue related to
7
what was discussed earlier is that I actually think
8
it might be a mistake not to include that group
9
because whatever happens with this study, that
10
group is going to be at excess risk of having this
11
done because they have excess benefit of having
12
this done.
13 DR. WEISS: So,
basically a historical
14
control of subjects in, let's say, your routine
15
cataract if we are talking about doing a minus 3
16
presbyope where you don't really expect there to be
17
much difference from people without previous ocular
18
surgery, but if you are doing the high risk
19
patients, let's say the minus 20 myope, in that
20
case you might want an active control.
If you were
21
doing a minus 20 myope, then neither of you would
22
like a historical control at that point and would
23
have an active control.
24 DR. FERRIS: It
is actually in the
25
company's benefit. This is one
of those places,
97
1
again, where you would like to have the control
2
rate because it is going to make your treated rate
3
look better because the control rate is actually
4
going to be significant.
Otherwise, I am assuming
5
the control rate is close to zero.
6 DR. WEISS: It
gets a little sticky from
7
the agency's standpoint--and correct me if I am
8
wrong--if we are speaking about a historical
9
control of subjects, except if we get involved in
10
certain refractive categories in which case now we
11
want to go on active control. Is
there any
12
guidance you can give us on that?
I guess we will
13
get involved in that when we get to question number
14
two. Dr. Brucker?
15 DR. BRUCKER: I
think that we are making
16
this very complicated and unnecessary.
17 DR. WEISS:
Welcome to the panel, Dr.
18
Brucker!
19 DR. BRUCKER: I
have been here and I will
20
tell you we are making it complicated and it need
21
not be. It seems to me that,
unlike some of the
22
comments around the table, these are patients who
23
will go elsewhere for refractive surgery. That is
24
not the case. These are patients
who are perhaps
25
45-55 years of age and, like myself, they are
98
1
starting to have to use glasses.
It is a pain in
2
the neck and it doesn't matter if they are minus 14
3
or plano like I am. The fact of
the matter is that
4
these are patients that could use glasses. There
5
is no reason that this isn't a randomization trial.
6
It will make things simpler for the sponsor. It
7
will make things simpler for the patient. It will
8
make things simpler for the FDA.
It makes things
9
simpler for everybody to get a group of patients
10
randomized and some will wear glasses.
Okay, they
11
have done it. It is only for
three more years.
12
And, some are going to have surgery.
I don't see
13
what the big deal is. The end
result is you are
14
going to have an idea. These
patients are not
15
going to have scleral depressed peripheral
16
examinations. You are not going
to know if they
17
have lattice. You are not going
to know what is
18
going on in the back of their eyes.
All you need
19
to do is take a look again at Ripandelli's paper.
20
Sixty percent of those patients wound up having
21
pre-treatment. It doesn't matter
if they are
22
pre-treated or not. It doesn't
matter what their
23
peripheral examinations are.
Randomize the
24 patients. Spread it out whether they are high
25
myopes, plano emmetropes or hyperopes.
Give them
99
1
all a chance to be in the study.
Make the sample
2
size large enough. Follow them
for three years and
3
you will have all of your answers and there weren't
4
be any complications or problems--let's not say
5
complications.
6 DR. WEISS: Mr.
McCarley?
7 MR. MCCARLEY:
I think a historical
8
cataract group would be fine unless the National
9
Eye Institute would be willing to fund and run a
10
study because it is actually the procedure we are
11
looking at, regardless of the intraocular lens.
12 DR. WEISS: I
have a feeling that is not
13
forthcoming. Now we are going to
go back; now that
14
we have heard everyone's opinions, some of our
15
opinions may have changed. Dr.
Bressler?
16 DR. BRESSLER:
I just wanted to clarify,
17
are we talking about active controls for safety or
18
efficacy? We haven't gotten to
the question of
19
what is the safety that we are looking at. So, I
20
know we are in a circle and jumping in.
I never
21
foresaw in suggesting active controls that you want
22
to power a study to see if there is a difference in
23
the retinal detachment rate. I
mean, that is low
24
in the non-high myope population and that would
25
take 40,000 or more and it wouldn't be meaningful
100
1
that you reduced it from 0.01 to 0.05 or something
2
like that in percentage.
3 So, for certain safety outcomes you may
4
have to deal with historical controls and there is
5
adequate information for some of those.
But for
6
other safety outcomes, for example changes in
7
visual acuity, you may be able to do it with
8
randomized controls so you don't have all the
9
confounding bias. As Rick
pointed out, it is true
10
that we had 3/50 in our limited information here
11
that lost one line by six months and that could be
12
noise; it may not be noise. It
may be the
13
beginning of two-line loss or three-line loss. It
14
was mainly in the hyperopes, not in the myopes in
15
that small study. That is 50
people versus--you
16
know, there are 60 million over the age of 65 that
17
are obviously going to be presbyopic.
18 So, I think it is incumbent upon the
19
safety, not the retinal detachment safety but some
20
of the others, to be aware of what these are; get
21
rid of the confounding bias and, although it may be
22
hard and take a little further discussion to get a
23 group
who is willing to put this off for a few
24
years until we know what the outcome is, there are
25
enough presbyopes out there--it is not a rare
101
1
disease--that it may be possible.
So, I just
2
wanted to add that clarification that I think I
3
agree with what most of the panel said but I am
4
still believing we would need for some of the
5
safety outcomes these controls.
6 DR. WEISS: I
am going to have one comment
7
from Dr. Maguire and then I am going to ask if the
8
agency needs anything more from us on this
9
question, just because we have eight of these to
10
get through. Dr. Maguire?
11 DR. MAGUIRE: I
have a question for the
12
agency. Does FDA separate groups
for presbyopic
13
correction if it is reasonable to expect that one
14
of those groups is more likely to have problems
15
with safety and efficacy, specifically the high
16
myope group? That would be a
reason to separate
17
them out. Is that correct?
18 DR. EYDELMAN:
In any refractive
19
indication we usually break it up into the ranges
20
of refractive error. For
example, for LASIK we
21 broke
it up to 7 and above 7, and emmetropia would
22
probably be analyzed separately.
So, yes, the data
23
would come in and then we would ask for internal
24
stratification of the data according to refractive
25
indication.
102
1 DR. MAGUIRE:
But you would still run the
2
study as a whole? In other
words, you wouldn't
3
place more stringent control requirements on
4
patients with high degrees of myopia than the
5
people with the other indications that led Dr. Lane
6
to say they shouldn't be included at all in our
7
discussion here.
8 DR. EYDELMAN:
Well, it is certainly up to
9
the sponsor to design what kind of trial they want
10
to do and what inclusion criteria they want to
11
expand their design to. We would
certainly take
12
your recommendations from today and try to give
13
guidance to the sponsor accordingly.
14 DR. WEISS: Dr.
Rosenthal?
15 DR. ROSENTHAL:
I know what Dr. Maguire is
16
getting at, and I think if there is a marked
17
discrepancy between two populations in the study
18
one would probably ask to look at both of them
19
together and then separately.
20 DR. WEISS: Dr.
Smith has a quick
21
question.
22 DR. SMITH: I
just wanted to clarify an
23
issue. In the first question
here we are talking
24
about clear lens extraction in the correction of
25
presbyopia.
103
1 DR. WEISS:
Yes.
2 DR. SMITH:
Some of those patients may be
3
myopic, hyperopic. We are not
talking about their
4
lens extraction for the treatment of high myopia.
5 DR. WEISS: We
have not gone to question
6
two, that is right.
7 DR. SMITH: But
this is clear lens
8
extraction and the indication is presbyopia. So,
9
that doesn't cover 25 year-olds who are minus 20.
10 DR. WEISS: You
are a hundred percent
11
right.
12 DR. SMITH: So,
I think that myopes are
13
complicating our discussion.
14 DR. WEISS:
Well, you might have a 50
15
year-old who is minus 20 and presbyopic.
16 DR. SMITH:
Right.
17 DR. WEISS: We
are going to then narrow
18
things down as we go on, hopefully, but right now,
19
from what I understand, most of the panel wants
20
controls. Most of the panel is
talking about
21
active controls. Some of the
panel is talking
22
about historical controls for safety and active
23
controls for efficacy, and some of the panel is
24
talking about randomization. I
would sort of like
25
to cut things off at this point because we have
104
1
eight questions and we have sort of gone over on
2
this one. Does the agency need
anything else from
3
us on that particular question?
4 DR. EYDELMAN:
No, thank you.
5 DR. WEISS:
Fine.