> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **DERMATOLOGIC AND OPHTHALMIC DRUGS**
>
> **ADVISORY COMMITTEE**
>
> **NDA 21-414, Vitrase (ovine hyaluronidase**
>
> **for Intravitreal Injection) by ISTA Pharmaceuticals**
>
> **for the Treatment of Vitreous Hemorrhage**
>
> Monday, March 17, 2003
>
> 8:00 a.m.
>
> Holiday Inn Gaithersburg
>
> Goshen Room
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Donald Fong, M.D., M.P.H., Acting Chair
>
> Kimberly Littleton Topper, M.S., Executive Secretary
>
> DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE
>
> MEMBERS
>
> Ming T. Tan, Ph.D.
>
> Paula L. Knudson, Consumer Representative
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> VOTING CONSULTANTS
>
> Emily Ying Chew, M.D.
>
> Jennifer A. Dunbar, M.D.
>
> Stephen Feman, M.D.
>
> Donald Fong, M.D., M.P.H.
>
> William G. Gates, M.D.
>
> William B. Phillips II, M.D.
>
> Scott Steidl, M.D., D.M.A.
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> NON-VOTING CONSULTANTS
>
> Eileen W. Ringel, M.D.
>
> Jimmy Douglas Schmidt, M.D.
>
> CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
>
> VOTING CONSULTANTS
>
> Jeremiah Brown, Jr., M.D.
>
> Jose Pulido, M.D.
>
> C. Pat Wilkinson, M.D.
>
> FDA
>
> Jonca Bull, M.D.
>
> Wiley A. Chambers, M.D.
>
> Jennifer D. Harris, M.D.
>
> Lee Simon, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Opening Remarks:
>
> Donald Fong, M.D. 4
>
> Conflict of Interest Statement:
>
> Kimberly Littleton Topper, M.S. 5
>
> Introduction:
>
> Wiley A. Chambers, M.D. 7
>
> Sponsor Presentation: ISTA Pharmaceuticals
>
> Introduction:
>
> Vicente Anido, Ph.D. 10
>
> Clinical Background:
>
> John W. Chandler, M.D. 13
>
> Study Design and Efficacy:
>
> Lisa R. Grillone, Ph.D. 20
>
> Safety:
>
> John W. Chandler, M.D. 41
>
> Investigators\' Perspective:
>
> Baruch D. Kuppermann, M.D. 51
>
> Edgar Thomas, M.D.
>
> Impact on Clinical Practice:
>
> Kirk Packo, M.D. 57
>
> Conclusions:
>
> Lisa R. Grillone, M.D. 61
>
> Questions from the Committee 63
>
> FDA Presentation:
>
> Jennifer D. Harris, M.D. 99
>
> Questions from the Committee 117
>
> Committee Discussion 157
>
> Open Public Hearing 167
>
> Committee Discussion 167
>
> Questions and Vote 207
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Opening Remarks**
>
> DR. FONG: Good morning. I am Donald Fong. I am the Chair of the
> Subcommittee on Ophthalmic Drugs. This morning, we are going to talk
> about a vitreous product from ISTA Pharmaceuticals. What I would like
> to do is start it off by introducing everybody on the committee. Maybe
> we can start on my left-hand side, start with our dermatologist, Dr.
> Schmidt.
>
> DR. SCHMIDT: I am Jimmy Schmidt from Houston, Texas.
>
> DR. RINGEL: Eileen Ringel from Maine.
>
> DR. TAN: Ming Tan, University of Maryland School of Medicine,
> Professor of Biostatistics.
>
> DR. PHILLIPS: Bill Phillips from the Washington, D.C. area.
>
> DR. WILKINSON: Pat Wilkinson from Baltimore.
>
> DR. PULIDO: Jose Pulido from Chicago.
>
> DR. GATES: William Gates, Nashville, Tennessee.
>
> DR. FONG: Donald Fong. I represent Kaiser Permanent, Southern
> California.
>
> DR. FEMAN: I am Steve Feman from St. Louis University in St. Louis.
>
> DR. DUNBAR: I\'m Jennifer Dunbar from Loma Linda University in
> California.
>
> DR. STEIDL: I\'m Scott Steidl from the University of Maryland in
> Baltimore.
>
> MS. KNUDSON: I\'m Paula Knudson from Houston, Texas.
>
> DR. HARRIS: Jennifer Harris, FDA.
>
> DR. CHAMBERS: Wiley Chambers, Deputy Division Director for the
> Division of Antiinflammatory, Analgesic and Ophthalmologic Drug
> Products.
>
> DR. SIMON: Lee Simon, Division Director for Analgesic,
> Antiinflammatory and Ophthalmologic Drug Products.
>
> DR. BULL: Good morning. Jonca Bull, Office of Drug Evaluation IV,
> Director.
>
> DR. FONG: I think we want to go back to Dr. Brown.
>
> DR. BROWN: Jeremiah Brown from San Antonio, Texas, University of Texas
> Health Sciences.
>
> DR. FONG: Kimberly, would you mind reading the Conflict of Interest
> Statement?
>
> **Conflict of Interest Statement**
>
> MS. TOPPER: The following announcement addresses the conflict of
> interest with regard to this meeting and is made a part of the record
> to preclude even the appearance of such at this meeting. Based on the
> submitted agenda for the meeting and all financial interests reported
> by the committee participants, it has been determined that all
> interests in firms regulated by the Center for Drug Evaluation and
> Research which have been reported by the participants present no
> potential for an appearance of a conflict of interest at this meeting.
>
> In the event that discussions involve any other products or firms not
> already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record.
>
> With respect to all other participants, we ask, in the interest of
> fairness, that they address any current or previous financial
> involvement with any firms whose products they may wish to comment
> upon.
>
> Thank you.
>
> DR. FONG: I also want to point out that Dr. Chew from the NIH will be
> here later one. She is stuck in traffic.
>
> Dr. Chambers:
>
> **Introduction**
>
> DR. CHAMBERS: Thank you. I would like to take this opportunity to
> welcome all of the committee members and the sponsor of the New Drug
> Application that we are discussing and the audience for what is a not
> particularly frequent advisory committee based on the fact that we
> have tried to be as selective as possible to try and respect
> everybody\'s time and bring to the committee just those issues where
> we have new indications, new classes of products, something relatively
> new to the area of ophthalmology.
>
> That is the case for this morning, or for today. In this particular
> case, we have not previously had applicants submit applications for
> issues involving bleeding within the eye or basically the treatment of
> any kind of vitreous hemorrhage, whether that is for just the
> treatment, whether that is for particular aspects of the indication,
> but any particular\--this is a new indication for us.
>
> The molecule that we are talking about is relatively old. There is a
> slight wrinkle, in this particular case, in that the source is not
> from bovine. It is from ovine. But the molecule is otherwise
> relatively well-known to members of this committee.
>
> Its use is new, and that is what we are going to primarily focus on.
> We will be talking about the clinical aspects of the New Drugs
> Application, not necessarily all of the pharm-tox or chemistry
> aspects, and, consequently, we will be asking for opinions on
> benefit-to-risk and particular aspects of this study design, the
> trials that were done, the results, the clinical utility.
>
> We do not expect, whether we get yes, no or indifferent from the
> committee today, to have that be the final decision on whether the
> application is approved or not approved. There are many other aspects
> that go into a New Drug Application such as the chemistry and
> manufacturing, such as some of the pharm-tox information, other parts
> that we will not be discussing today.
>
> What we are keying on is the area we believe you have expertise to
> help us with and that is in the area of the clinical results and the
> clinical utility. We thank you for helping us with that expertise.
>
> We are as interested in the discussion that goes on and comments that
> you have as any particular votes. There will be a number of votes and
> particular questions being asked to you, but we are just as interested
> in the discussion that goes along with all this and there are minutes
> being taken as well as a transcript being prepared which is why we ask
> everybody to try and use the microphones and speak as clearly as
> possible and identify yourself if you haven\'t already been introduced
> as you first come on to help the transcriptionist with the recordings.
>
> At any point along, if there are any questions, please feel free to
> ask either the Chairman, Dr. Fong, or myself or anybody else on the
> FDA staff and we will try and help out and try and make things run as
> smoothly as possible.
>
> Again, thank you for your time. I will turn it back over to Dr. Fong.
>
> DR. FONG: Thank you, Wiley.
>
> Next up is the presentation from the sponsor.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. ANIDO: Good morning.
>
> \[Slide.\]
>
> My name is Vince Anido. I am the President and CEO of ISTA
> Pharmaceuticals. It is our pleasure to be here today. My role is
> relatively simple and that is to basically share with you our agenda
> for the next sixty minutes or so.
>
> Before I do that, I would like to first of all take the opportunity to
> thank Dr. Bull, Dr. Simon, Dr. Chambers, Dr. Harris and the members of
> the FDA team for all the support and help that they have provided
> getting us to this point, and also Dr. Fong and the Advisory members
> for their time that we will be spending on this application today.
>
> \[Slide.\]
>
> ISTA is a specialty pharmaceutical company with a focus on
> ophthalmology.
>
> \[Slide.\]
>
> We believe, and we will be showing you data today that support the
> approval for the treatment of vitreous hemorrhage for our product
> Vitrase. It is for the treatment of vitreous hemorrhage not only to
> improve visual acuity but also to facilitate the physician\'s ability
> to diagnose the underlying disease.
>
> This will be the first pharmaceutical product approved in this
> particular category.
>
> \[Slide.\]
>
> Vitrase is a single injection intravitreous, highly purified ovine
> hyaluronidase. We have been working on this for roughly about ten
> years and, in that time frame, we have actually dosed up to 1,500
> patients in about thirteen countries.
>
> \[Slide.\]
>
> The development history of the product pretty much spans the history
> of our company. We were founded in 1992 and that is when we started
> working on hyaluronidase for ophthalmology applications. One of the
> significant events for us was the fast-track designation that we
> received in 1998 which then allowed us to submit sections of the NDA
> throughout the Year 2002. That was the preclinical, clinical and the
> CMC sections. Obviously, that is what ha gotten us here today.
>
> \[Slide.\]
>
> The presentation for us will as follows: the clinical and the disease
> background will be provided by Dr. Jack Chandler. Jack has been a
> consultant to ISTA for the last two years. Prior to that, he was the
> Past Chair and Professor of Ophthalmology at both the University of
> Illinois and the University of Wisconsin.
>
> Dr. Lisa Grillone, who is our Vice President of Clinical Research and
> Medical Affairs, will then go through the data from the Phase II
> studies and show you the efficacy of the drug. Dr. Chandler will then
> come back and talk about the safety of the product.
>
> After that, we will go through and have Dr. Barry Kupperman, who is
> Associate Professor at the University of California at Irvine in the
> Ophthalmology Department, and Dr. Gary Thomas, a vitreoretinal
> specialist in one of the largest practices in Los Angeles, will talk
> about the investigators\' perspective. They were the lead
> investigators for our product in the U.S.
>
> After that, Dr. Kirk Packo will talk about the impact of our drug on
> ophthalmology practice in general. Kirk is Associate Professor of
> Ophthalmology at Rush Presbyterian. He is the Immediate Past President
> of the American Society of Retina Specialists. After that, Dr. Gillone
> will wrap up on conclusions.
>
> \[Slide.\]
>
> For the Q&A Section, in addition to the various presenters that we
> have, we have two other gentlemen, Dr. Ray Buck who is a statistical
> consultant for us from Cato Research, is available to answer questions
> as is a member of our DSMB, our Data Safety Monitoring Board, Dr.
> Brooks McCuen who is with Duke University.
>
> \[Slide.\]
>
> From the company available to answer questions will be, in addition to
> Dr. Grillone and myself, Mr. Marv Garrett who is the Vice President of
> Regulatory Affairs, Quality and Assurance; Bill Craig, who is a V.P.
> of Research and Product Development; and Kirk McMullin, who is Vice
> President of Operations.
>
> \[Slide.\]
>
> Now I will turn it over to Dr. Chandler.
>
> **Clinical Background**
>
> DR. CHANDLER: Ladies and gentlemen, good morning and Happy St.
> Patrick\'s Day. Fort past two years, I have been serving as a
> consultant for ISTA Pharmaceuticals as a member of their Clinician
> Advisory Board serving and working on the preparation of this NDA,
> especially the safety sections, and was the Chairman of the Efficacy
> Evaluation Committee in the past several months.
>
> \[Slide.\]
>
> Spontaneous vitreous hemorrhages that are severe, based on one study,
> a prospective study, appear to occur in about 7 per 100,000 population
> on an annual basis. For the United States, this translates to
> approximately 20,000 more patients with vitreous hemorrhages entering
> the pool each year.
>
> \[Slide.\]
>
> The common causes, most of which lead to unilateral but not always
> vitreous hemorrhage, include proliferative diabetic retinopathy,
> posterior vitreous detachments with or without a tear or detachment,
> trauma, branch or central retinal vein occlusion, retinal
> macroaneurysm, age-related macular degeneration and subarachnoid
> hemorrhage.
>
> \[Slide.\]
>
> 63 percent of the bilateral cases are related to proliferative
> diabetic retinopathy. Except for trauma and subarachnoid hemorrhages
> where the retina is usually normal, there is usually preexisting
> retinal pathology in the other etiologies.
>
> \[Slide.\]
>
> In terms of mechanisms of vitreous hemorrhage, tear can happen in
> normal blood vessels, vessels from neovascularization or disease. As
> well, they can occur from other sites such as the choroid.
>
> \[Slide.\]
>
> The sequelae include decreases in visual acuity for the patient. For
> the ophthalmologist, it obstructs visualization of the posterior pole,
> prevents therapy of sight-threatening pathology such as retinal and
> choroidal neovascularization and causes, in an experimental model in
> nonhuman primates, at least, the blood in a large hemorrhage directly
> seems to cause retinal pathologic changes and electroretinographic
> abnormalities.
>
> \[Slide.\]
>
> Natural-history studies give us an opportunity to look at the
> consequences of vitreous hemorrhages. I will show you three that are
> very illustrative of this.
>
> \[Slide.\]
>
> A study of 85 untreated large vitreous-hemorrhaged eyes in the United
> States showed that 70 percent, at three to ten years of follow up, had
> no better than 5/200 vision.
>
> \[Slide.\]
>
> In Spain, a similar study looking at untreated massive vitreous
> hemorrhages showed that, compared to baseline, 26 percent had improved
> at three months but 74 percent were worse or unchanged. At two years,
> with no treatment, half of the patients were worse than hand motion
> and only 21 percent were better than hand motion.
>
> \[Slide.\]
>
> The DVRS study, the diabetic retinopathy vitrectomy, which was an NEI
> collaborative trial, had an arm that dealt with severe vitreous
> hemorrhage that included 312 eyes, as you are all well aware. Half
> were randomized to immediate treatment after the detection and
> randomization was taking place for hemorrhages that were roughly at
> least six months in duration. Visual acuity was similar to what we
> have in our Phase III studies.
>
> \[Slide.\]
>
> The delayed arm is what I am talking about that gives us a look at a
> natural history where vitrectomy was delayed for one year. In that
> group, 22 percent had the hemorrhage clear sufficiently that they
> didn\'t need the vitrectomy at one year. 11 percent had vitrectomies
> to deal with traction, retinal detachments. 5 percent, during that one
> year, became inoperable for such things as complicated retinal
> detachments and neovascular glaucoma.
>
> \[Slide.\]
>
> So we have currently, in our armamentarium as ophthalmologists,
> natural history, watchful waiting, whatever you want to talk about,
> where there is poor clearance, an inability to diagnose and treat the
> condition. While it is untreatable, there is progression of the
> underlying pathology and, for a vast majority of these patients, there
> is a poor visual outcome, not just short term but long term, as we saw
> in the first study.
>
> Currently, there is no pharmaceutical treatment for vitreous
> hemorrhage. That is the role we are talking about today for Vitrase.
>
> \[Slide.\]
>
> On the other hand, and you are all very aware of it, is vitrectomy, a
> major ocular procedure. Some eyes and patients are a poor risk. It is
> costly. There can be serious complications. In the DRVS, which was
> quite a while ago, now, they were as high as 30 to 40 percent. Given
> today\'s modern techniques and instrumentation, obviously, that rate
> is much lower but it is not eliminated. There are still serious
> complications with vitrectomy.
>
> \[Slide.\]
>
> In looking at and conceiving of where Vitrase would play a role, the
> following goals were set, that it would be safe, that it would speed
> the hemorrhage clearance, help restore visual function, allow early
> therapy of the underlying pathology when it was there, and it would
> not preclude future vitrectomy and that it would be an office
> procedure that was widely available.
>
> \[Slide.\]
>
> For the patient, this means, if Vitrase meets these goals, that there
> will be earlier diagnosis and treatment, earlier return of visual
> function for those with unilateral hemorrhage, and you will hear, on
> the videotape, a wonderful discussion of this by a patient, an
> improvement in their visual function. It is self evident, I think, for
> the patients with bilateral hemorrhages that this would be a marked
> help to them.
>
> \[Slide.\]
>
> As has been mentioned, Vitrase is highly purified ovine testicular
> hyaluronidase. It is prepared, preservative free, and it is then made
> up with sterile sodium chloride, the same sodium chloride that was in
> our saline placebo treatment arm. This is not the same, obviously, as
> a natural history, no treatment option, as people have now.
>
> \[Slide.\]
>
> Pharmacokinetics have been looked at in animal studies following
> intravitreous injection. The half-life in plasma is 49 hours. The
> highest concentrations are achieved in vitreous, retina and sclera.
> The half-life in ocular tissues is somewhere between 60 and 112 hours,
> roughly two to four days.
>
> \[Slide.\]
>
> In terms of the mechanisms of hyaluronidase, we know that it cleaves
> glycosidic bonds of hyaluron to form low-molecular-weight hyaluron.
> You can speculate down the rest of the way, although not fully proven,
> that it leads to collapse and liquification of the vitreous. It
> facilitates diffusion of molecules including proinflammatory
> chemotactic factors, that it promotes the ingress of phagocytic cells
> and the egress of red blood cells and red-blood-cell breakdown
> products in proteins.
>
> \[Slide.\]
>
> In a schematic fashion here, and with actual clinical photos here, you
> can see what we conceive of as happening with treatment with Vitrase.
> To look at the clinical photos, this was taken the day of and just
> before, just prior to, Vitrase injection. This is eight days following
> it, and three weeks.
>
> What you see is a large\--typical of the hemorrhages that we had at
> the onset covering critical areas of the posterior pole and breaking
> up of the hemorrhage and egress of red blood cells actually happening
> in some patients quite rapidly, others slower. But this is what the
> concept of what Vitrase does following an intravitreous injection.
>
> \[Slide.\]
>
> Next, we are going to turn to talking about the Phase III trials,
> study design and efficacy results by Dr. Lisa Grillone.
>
> **Study Design and Efficacy**
>
> DR. GRILLONE: Thank you, Dr. Chandler, and top of the morning to
> everybody here this morning. Today, I am going to provide for you
> efficacy results for Vitrase for the treatment of vitreous hemorrhage.
>
> \[Slide.\]
>
> Two Phase III studies were conducted, controlled clinical trials,
> double-masked, placebo-controlled in 131 sites in which patients were
> contributed to the intent-to-treat population. Overall, across twelve
> countries, we accumulated 1,306 patients.
>
> You will see here that there were four doses, at least in one of the
> studies, in the North American study. These doses included 7.5, 55, 75
> IU Vitrase compared to saline.
>
> \[Slide.\]
>
> In the Ex North American study, the 7.5 International Unit dose group
> was not included. For the Ex North American study, 556 patients from a
> total of many centers in nine countries contributed to the
> intent-to-treat population.
>
> \[Slide.\]
>
> In the North American study, conducted in the United States, Canada
> and Mexico, 750 patients contributed to the saline-controlled
> intent-to-treat population study. I will also point out to you here,
> on the right-hand side, you see some numbers. This is the watchful
> waiting control study that was the initial protocol begun several
> years ago. This study, once it had accumulated 71 patients in which
> the control arm was a watchful waiting, no treatment, arm. This study
> was discontinued and the saline control study was reinitiated to
> enroll the 750 patients.
>
> \[Slide.\]
>
> Presentation today will focus on study design, efficacy measures,
> which I will define for you. Patient demographics and characteristics
> will be presented and three-month efficacy results will be presented
> as well. When Dr. Chandler comes back and presents safety data, that
> will be all of the safety included in the NDA submission for all of
> the patients at that time.
>
> \[Slide.\]
>
> Vitrase efficacy. Today, I am going to show you results from two
> controlled clinical trials that will demonstrate and confirm that we
> see clinical efficacy in four efficacy measures early. The first
> efficacy measure will be reduction in hemorrhage density; second,
> improvement in best-corrected visual acuity; third, an outcome by
> investigator which is the surrogate success endpoint without the
> documentation by the investigation and, of course, the primary
> efficacy endpoint which was surrogate success.
>
> You will see results in two separate trials, the arrows here
> indicating statistical significance, that we reached statistical
> significance early, at Month 1, and that that efficacy was confirmed
> in three of the four parameters through Month 2 and, in some cases,
> even as far out as Month 3.
>
> \[Slide.\]
>
> Let\'s begin with the eligibility criteria. Patients for this trial
> had to come in to the study with a hemorrhage for at least one month,
> but I will show you, in a minute, that actually many of these patients
> had hemorrhages that were much older than one month. As well, the
> hemorrhage had to be severe at study entry. Severity would be a Grade
> 3 or a 4 that would obscure visualization of the fundus, and I will
> define that better for you in a minute. Of course, the best-corrected
> visual acuity would worse than 20/200 in the study eye.
>
> \[Slide.\]
>
> Hemorrhage severity of Grade 3 or 4 in all twelve clock hours was
> defined for a Grade 3, for example, as a red reflex that would be
> visible without central retinal-vein detail posterior to the equator.
>
> \[Slide.\]
>
> Let me give you an example. This would be a nonqualifying hemorrhage
> because, while we see blood in the vitreous, you can see retinal
> detail posterior to the equator. I am not sure that you can see it
> here and there is a little bit of detail that you can see there.
>
> \[Slide.\]
>
> This would be a Grade 3 qualifying hemorrhage even with headlight in
> the fog visible. This, of course, is a Grade 4 qualifying hemorrhage.
>
> \[Slide.\]
>
> Exclusion criteria. Primarily, if the patient had a retinal
> detachment, ocular trauma, vitrectomy and especially if there was no
> light perception in either eye.
>
> \[Slide.\]
>
> For your information, this study was studied by a data safety
> monitoring board chaired by Dr. Tom Fleming. Members of the board
> included Rick Ferris, Brooks McCuen and Alan Byrd. They conducted four
> interim analyses at which they evaluated both safety and efficacy. At
> all four interim analyses, they recommended continuation of the study.
>
> \[Slide.\]
>
> Patients were randomly assigned to receive a single intravitreous
> injection, a 50-microliter injection, in one eye. Three or four
> treatment groups, as I mentioned previously and as a reminder, the Ex
> North American study did not have a 7.5 IU dose group. The two doses
> in common to the two trials, then, were 55 and 75 versus the saline
> control.
>
> \[Slide.\]
>
> Efficacy measures. Reduction in vitreous-hemorrhage density. Certainly
> this is important to the physician because it demonstrates that there
> is clearance of the hemorrhage sufficiently to evaluate the underlying
> retinal pathology. Improvement in best-corrected visual acuity, which
> I will define shortly, an outcome determined by the investigator,
> simply the clearance of the hemorrhage with diagnosis and treatment if
> required. This is the same as the surrogate success endpoint which was
> the original primary efficacy endpoint except that there is no
> requirement in the outcome here for documentation by the physician
> whereas the requirement, and this is an important distinction, in the
> surrogate success evaluation, there was a requirement for the
> investigator to document clearly that the laser treatment had been
> completed.
>
> \[Slide.\]
>
> So, while the surrogate success primary endpoint was success on or
> prior to Month 3, and that success being a clearance in hemorrhage
> sufficiently to diagnose, see the underlying retinal pathology and
> complete the appropriate laser treatment.
>
> There had to be documentation that the laser treatment was completed
> or, for example, if no treatment was required and a fundus photograph
> had to be taken, there was a requirement that that fundus photograph
> had to be adequate. So, if you had a patient and the fundus photograph
> was missing or not clear, that patient would be a treatment failure in
> the surrogate success but a treatment success in the outcome by
> investigator, an important distinction.
>
> \[Slide.\]
>
> There are several major shortcomings with the surrogate success
> endpoint. While it was our primary endpoint, in point of fact, there
> were several things that had to be taken into consideration. Data from
> the Phase IIB clinical trials suggested that efficacy would be
> met\--that is clearance of the hemorrhage sufficient to diagnose and
> treat\--by Day 56.
>
> When these Phase III studies were planned, the sponsor thought that it
> would be better to extend that Day 56 time point to 90 days in order
> to secure that documentation from the investigator. In point of fact,
> you will see in a minute that we had efficacy much earlier rather than
> later.
>
> \[Slide.\]
>
> Again, outcome by investigator simply does not require documentation
> in the case report form that the treatment was completed.
>
> \[Slide.\]
>
> Reduction in hemorrhage density required that the appropriate number
> of clock hours, six if the patient had proliferative diabetic
> retinopathy, had a clearing to a Grade 0 or 1, and, for patients who
> had branch retinal-vein occlusion, that clearing was appropriate in
> three clock hours, thus allowed the appropriate territory for laser
> photocoagulation.
>
> \[Slide.\]
>
> What does that look like? On the left here, a Grade 0, where you can
> see complete clearance, and, on the right, while you have some blood
> in the lower portion here, clearly there is sufficient area for the
> physician to do laser photocoagulation.
>
> \[Slide.\]
>
> We required this. Again, as I say, a Grade 0 or 1 and at least six
> clock hours, or 0 or 1 in three clock hours for those patients with
> branch retinal-vein occlusion.
>
> \[Slide.\]
>
> Certainly, the most important and principal efficacy endpoint is
> improvement in BCVA. While the surrogate success endpoint was not an
> endpoint that was accepted by the agency because we could not provide
> a complete validation for this protocol, the improvement in
> best-corrected visual acuity is an efficacy endpoint that is accepted.
> Here, we looked at a minimum of at least a three-line improvement or
> 0.3 logMAR units where each letter is 0.02 logMAR units.
>
> For those patients who were not able to read on chart, for those
> patients who had off-chart visual acuity\--in other words, those
> patients who might have light perception or hand motion at study
> entry\--and you will see, in a minute, that there were quite a number
> of those\--we took a very conservative approach because there was no
> protocol-defined method for illumination and target distance and so
> forth.
>
> So, because of that, we took the conservative approach that light
> perception to hand motion would count as a one-line improvement and
> hand motion to count fingers would be a second line and then count
> fingers to reading any letter on the chart would be the third line of
> improvement.
>
> \[Slide.\]
>
> Improvement in best-corrected visual acuity, of course, answers an
> important clinical question; is there a meaningful improvement in the
> patient\'s vision resulting from the hemorrhage density clearance.
> Reduction of hemorrhage density clearance of 0 or 1 clock
> hours\--sorry.
>
> \[Slide.\]
>
> Roadmap. I will present all of the data in the following order. Study
> sequence will be Ex North American, then the North American study and
> then the two studies integrated.
>
> \[Slide.\]
>
> Let\'s begin with the patient demographics. You will see that there is
> no apparent difference between the Ex North American, North American
> and the Integrated dataset for the two doses in common, 55 and 75, for
> gender or age. Ethnicity for Caucasian, black or Asian while, in the
> category \"other,\" in the North American study, 40 percent of the
> patients checked this category.
>
> That represents primarily the 33 percent of the patients in the North
> American study that were Hispanic from the Mexican sites and several
> other sites with a high Hispanic population.
>
> \[Slide.\]
>
> Etiology of the baseline vitreous hemorrhage. First of all, more than
> 70 percent of the patients had proliferative diabetic retinopathy. 15
> to 20 percent of the patients had central retinal-vein occlusion or
> branch retinal-vein occlusion or exudative macular degeneration, and
> the remainder in the other categories.
>
> \[Slide.\]
>
> I mentioned earlier, when I mentioned that vitreous hemorrhage
> duration had to be at least one month, that, in fact, the duration was
> closer to four months. You can see by the standard deviation that the
> range was quite high. Not only did the majority of patients have a
> hemorrhage duration longer than a mean of at least four months, but
> several, many, had a hemorrhage duration of much longer than that
> period of time.
>
> \[Slide.\]
>
> Baseline diabetic status. While 24 percent of the patients were
> nondiabetic, and I remind you that these studies were not stratified
> by diabetic status, more than 75 percent of the patients were diabetic
> at study entry. This is important because we found some interesting
> results in this subgroup, in the diabetic subgroup, population.
>
> \[Slide.\]
>
> Now, the off-chart visual acuity. More than 90 percent of the
> patients, overall, could not read one letter on chart; that is, more
> than 90 percent of the patients could only have vision of light
> perception, hand motion or count fingers at study entry, an important
> point to keep in mind when we look at the changes in best-corrected
> visual acuity.
>
> \[Slide.\]
>
> Let\'s begin with the study data. Again, the original primary efficacy
> endpoint, surrogate success on or prior to Month 3.
>
> \[Slide.\]
>
> I would like to point out two things at this point before\--I will
> begin the graph in a minute, but in your package, you have tables
> after every one of the graphs that simply describe the numbers and the
> absolute p-values. I will not present the tables, in the interest of
> time, today. I will present all the results graphically.
>
> Furthermore, Dr. Chandler, when he presents safety data, some of the
> numbers that you have are just percentages and I think, in one of your
> earlier packets, you also have the n\'s go appropriately with that
> package. I believe you can see which slides we have hit it in the
> interest of time.
>
> Let\'s look at the graph for a minute. I will just set this up for
> you. On the X axis, we have time. These will be cumulative data at
> Month 1, Month 2 and Month 3. On the Y axis is the proportion of
> patients achieving the efficacy measure in question at the moment.
> Saline will always be a blue line. 55 will be a yellow and 75 will be
> a red line.
>
> One asterisk will mean statistical significance to less than 0.05 and
> two asterisks will mean significance to less than 0.005.
>
> So if we begin with the Ex North American study, the saline group, as
> you see here, and the 55 IU group seen here. I will point out here
> that we see, again, while we did not reach statistical significance at
> the Month 3 time point, in fact, in this study, we reached the
> significance early at Month 1. Whenever you see letters enlarged in
> the asterisk, that denotes that there is statistical significance
> compared to saline.
>
> Here is the 75 IU dose group which, while it did not meet statistical
> significance, certainly, by three months, was in the same trend as the
> 55 IU dose group.
>
> \[Slide.\]
>
> For the North American study, this is saline. Now, we have a 7.5 IU
> dose group in this and we see, again, at the low dose group,
> significance early at Month 1, the 55 IU dose group and the 75 IU dose
> group, both of these doses reaching significance at Month 1 and Month
> 2.
>
> So, while the significance was not reached at the Month 3 time point,
> we have nearly 40 percent of the patients, nevertheless, who did. But
> the important point here is not that we missed at three months. It is
> not that we got it later. Contrary, we actually reached this endpoint
> earlier than we anticipated.
>
> \[Slide.\]
>
> If we look at the dataset pooled for saline, and 55, which is in
> common, we see significance at all three time points. At 75, we see
> significance at Month 1.
>
> \[Slide.\]
>
> Now to the outcome by investigator. Again, the only difference here,
> compared to the surrogate success, is that this did not require the
> documentation. So that if the photograph was missing but the
> investigator said that there was treatment success and that they had
> taken the photograph, we counted this patient as a success.
>
> \[Slide.\]
>
> If we look at the Ex North American study for saline, for the 55 IU
> dose group, clearly the investigators thought that there was success
> at Month 1, Month 2 and Month 3. For the 75 IU dose group, while we
> didn\'t reach treatment success statistical difference, we see the
> same trend as in the 55 IU dose group.
>
> \[Slide.\]
>
> In the North American study, for the same outcome, saline, 7.5, having
> a treatment effect reaching statistical significance again at all
> three months at 55 and 75. So, in all three dose groups in this case,
> we reached statistical significance for the outcome determined by
> investigator.
>
> \[Slide.\]
>
> In the Integrated dataset for saline and the two dose groups in
> common, 55 and 75, you can see that there is an early treatment
> effect. Again, the investigators clearly believe there was a treatment
> effect and that treatment effect was evident, 40 percent of the
> patients reaching statistical significance out to about the
> three-month time point.
>
> \[Slide.\]
>
> Now lets turn our attention to the reduction in vitreous-hemorrhage
> density. This is the outcome that is important to the physician
> because it tells us how much of the hemorrhage has cleared and if
> sufficient amount has cleared for the underlying retinal pathology to
> be treated.
>
> \[Slide.\]
>
> In the Ex North American study for saline, for 55 and for 75 IU dose
> groups, we see a treatment effect for the 55 IU dose group early
> persisting through three months where we see a statistically
> significant difference in nearly 40 percent of the patients reaching
> this outcome.
>
> \[Slide.\]
>
> In the North American study, similarly for saline, first, then, 7.5,
> 55 and 75 IU dose groups. For the two low-dose groups, we see this
> treatment effect again early, at Month 1, through to Month 2, for the
> high-dose group, 43 percent of the patients, approximately, having a
> statistically significant difference in treatment effect out at three
> months.
>
> \[Slide.\]
>
> When we integrate the two studies for this outcome, we see, for 55,
> there is a statistically significant impact compared to saline both
> early and for the longer time points and, as well, for the 75 IU dose
> group. Where we see that treatment effect, we see the reduction in
> hemorrhage density to nearly 40 percent of the patients by the three
> month time point.
>
> \[Slide.\]
>
> Now lets move to the improvement in best-corrected visual acuity. We
> consider this the principal efficacy measure. This gives us
> information about well the patient could see in the condition of a
> reduction in vitreous-hemorrhage density. While I will show you a
> minimum of a three-line improvement, I will tell you also that we have
> several analyses where we look at not only 15 letters improvement, how
> many of the patients could read 15 letters on chart and, as well, how
> many of the patients had 20/200 or better vision in eyes, keep in
> mind, that had no visual acuity except for light perception, hand
> motion or count fingers at study entry.
>
> \[Slide.\]
>
> So the three-line improvement, minimally, in the Ex North American
> study for saline, now for the 55 IU dose group, beginning with about
> 33 percent of the patients who had at least a three-line improvement,
> reaching nearly 50 percent of the patients, 46 percent of the
> patients, at the three-month time point who had an improvement
> statistically significant difference and at least a three-line
> improvement by three months and the 75 IU dose group in the Ex North
> American study, where we consider these two numbers, while 42 percent
> is not statistical difference from 32 percent in the saline group, we
> consider these two values to be quite similar.
>
> \[Slide.\]
>
> In the North American study, for saline, for 7.5, for 55 and for 75,
> in all three dose groups, we see at least a three-line improvement
> early, one month after a single intravitreous injection, and this
> effect persisted through to two months for the two high-dose groups.
>
> \[Slide.\]
>
> When we look at the Integrated dataset as well, for saline, for 55 and
> now for 75, again, in both dose groups in the Integrated dataset, this
> treatment effect appears early. It is the minimal improvement in BCVA
> that we evaluated. Nearly 50 percent of the patients, 45 percent of
> the patients, maintained that treatment effect through to Month 3.
>
> \[Slide.\]
>
> We did a confirmatory analysis for this improvement in best-corrected
> visual acuity. While you recall that, when I began, I said that if
> patients went from count fingers to reading just one letter on chart,
> we would count that as a one-line improvement.
>
> We also did something called read letters as is, in which case we took
> the number of letters read correctly on that first line plus the
> distance at which the letters were read and we counted that. We
> calculated a logMAR unit score and called that read letters as is. So
> it is an absolute score.
>
> In this case, for the integrated dataset shown here, you can see that
> there is a highly statistically significant difference for both doses
> at all three time points for those patients with read letters scored
> as is.
>
> \[Slide.\]
>
> What have I shown you in the Ex North American study? First, that
> there is an early response to Vitrase in the treatment of vitreous
> hemorrhage. Whether we measure it by a reduction in
> vitreous-hemorrhage density, statistically significant at Month 1,
> improvement in best-corrected visual acuity, the same, a statistically
> significant difference at Month 1. Outcome by investigator and
> surrogate success, all statistically significant at Month 1.
>
> At the 55 unit dose as well, this outcome, this statistically
> significant difference persisted through Month 2 and Month 3 for three
> of the four outcomes, the only difference in the surrogate being that
> there wasn\'t adequate documentation by the investigator in the case
> report form.
>
> We confirmed these results in the North American study where,
> similarly, we see, for all four efficacy measures, an early treatment
> effect, earlier than we anticipated, Month 1. This treatment effect
> persisted for all four categories of efficacy through Month 2 and for
> a few of the categories, reduction in vitreous-hemorrhage density and
> the outcome by investigator even out to Month 3.
>
> \[Slide.\]
>
> When we look at the integrated dataset as well, we can see that there
> is confirmatory evidence here, when we pool the datasets, that, in all
> four categories, we see a statistically significant difference not
> only early but one that persists and continues through three months of
> evaluation following such a single intravitreous injection of Vitrase.
>
> Thank you.
>
> \[Slide.\]
>
> I would like to turn the microphone over to Dr. Chandler for the
> safety assessment.
>
> **Safety**
>
> DR. CHANDLER: The safety of Vitrase was determined on the basis of
> analyses of ophthalmologic examinations that were protocol-determined
> and recorded in the case report form at each visit plus adverse-event
> reports.
>
> By prior agreement with the agency, systemic examinations and
> laboratory studies were not conducted. All of the adverse events, both
> systemic and ophthalmic or ocular, were coded using Medra. All coding
> was done without knowledge of treatment assignment.
>
> \[Slide.\]
>
> The safety population consisted of all patients who received a single
> intravitreous injection in the Phase III studies. In Ex North America,
> that included 551 patients and in, North America, it included
> 740 patients from the saline controlled study.
>
> \[Slide.\]
>
> Then we had an early study which had a watchful-waiting arm in which
> 17 or 18 patients were in each of the four arms. I am reporting the
> safety data on the 53 patients from that small study that received an
> intravitreous injection.
>
> So the total study population is 1,344 eyes that were injected. In
> none of those eyes was there injection-related endophthalmitis.
>
> \[Slide.\]
>
> This just gives you, in an integrated fashion, the follow-up that we
> used. Dr. Grillone earlier indicated that, at the time that this cut
> of data was done, all patients had reached at least the three-month
> visit point. This occurred at the end of September of 2001.
>
> The mean days of follow up is quite similar. You will notice that the
> Vitrase 7.5, that smaller dose, had a longer, about 50 day longer,
> follow up as a mean in terms of patients that had at least six-months
> data. It was 70 percent to 75 percent. In terms of those, at that
> point, that had twelve-month follow up or longer, it was 45 to
> 50 percent. In terms of the two higher doses, 372 patients had been
> looked at for at least one year.
>
> \[Slide.\]
>
> The deaths did occur in this population, as expected. You will recall
> that three-quarters of these patients had proliferative diabetic
> retinopathy and that the mean age at enrollment was 62 years. The
> primary causes of death were related to hypertension, cardiovascular
> disease and, in some cases, renal failure.
>
> I will speak to this in just a moment, but here are the deaths across
> studies and integrated. Remember that this arm, I told you, had
> eighteen patients and there have been up to the time of the data
> analysis, six deaths. We have looked at all deaths in detail. They all
> appear to be related to their systemic underlying disease. There were
> none that appear in any way related to Vitrase or any other events
> related to the study.
>
> \[Slide.\]
>
> Looking at eyes, remember that eyes had to have at least light
> perception and no better than 5/200 vision at the time of entry. This
> gives you the picture of eyes that have progressed to no light
> perception during that follow-up period I just described to you. It is
> not statistically significant for either the Ex North American study
> or the North American study. When you integrate, you can see, again
> keeping in mind, that this was a very small study relative to
> everything else, that these eyes tended to do quite well.
>
> Again, the 7.5 Vitrase group was in North America. Again, this is an
> 18-patient arm here that gives you, I believe, based on the small
> population, a spurious result.
>
> \[Slide.\]
>
> In terms of systemic adverse events, in the Ex North American study,
> none of them achieved a 10 percent or greater incidence in the
> combined Vitrase groups that were studied.
>
> In North America, there were four; infections and infestations,
> nervous-system disorders, cardiac disorders and gastrointestinal
> disorders. Again, you will see that there was not a statistically
> significant difference between the saline control patients and those
> that received Vitrase.
>
> \[Slide.\]
>
> In terms of discontinuation due to serious adverse events, they were
> all over the map and don\'t appear to give us any hints about
> something regarding Vitrase that leads to serious adverse events that
> require discontinuation. We will look at that in a different way in a
> moment.
>
> \[Slide.\]
>
> If you look at ocular serious adverse events that achieved a 5 percent
> or greater incidence.
>
> \[Slide.\]
>
> In the integrated study, you find four; recurrent vitreous, or rebleed
> of a vitreous hemorrhage, retinal detachment, rubiosis and increased
> intraocular pressure.
>
> \[Slide.\]
>
> You will see that, for vitreous hemorrhage that has recurred or
> rebled, there is a higher incidence in the Vitrase-treated groups. It
> is not statistically significant and it perhaps relates to the fact
> that there was more efficacy in this group and clearing of hemorrhage
> so it was very apparent when there was a rebleed. The
> retinal-detachment rates are very similar. Rubiosis, as you can see,
> is very similar across groups. Increased intraocular pressure; again,
> this smaller group with longer follow up had slightly more in it.
>
> Most of the times, these were one or two readings that were above 23
> millimeters of mercury and returned to normal. The only real big one
> was one patient who had preexisting primary open-angle glaucoma that
> was removed from the study because of the problems a few weeks after
> the injection.
>
> \[Slide.\]
>
> Adverse events. If you look at the Ex North American study, events
> that achieved a 10 percent or greater incidence and were statistically
> significant between saline and the Vitrase groups, it came down to a
> very few that did this. I want to point out, though, that, in this
> study, whether you were in the saline control group or the 55 or 75
> treatment groups, there were frequent reports of ocular events.
>
> \[Slide.\]
>
> I think we can safely and reasonably agree that, with iritis,
> hyperemia and pain were typical travelers. You see that as you look at
> these over time. These eyes with iritis, and we will talk about this
> more, were not really hot eyes. The pain was not incapacitating. The
> hyperemia was often localized more around the injection site. These
> tended to occur early.
>
> \[Slide.\]
>
> Here is the North American, same parameters; greater than 10 percent
> incidence and a statistical significance between the saline group and
> the Vitrase-treated eyes. In North America, events were reported more
> frequently for patients. Between 91 and 99 percent of the patients had
> at least one reported ocular adverse event.
>
> \[Slide.\]
>
> I think you would agree, again, that this group traveled together.
> Let\'s talk about the iritis for just a moment. The iritis tended to
> curve very early after the injection. It tended to not persist. It was
> easily managed, in many cases, with no treatment at all or with
> topical medications including corticosteroids, cycloplegics and, in a
> few cases, nonsteroidal antiinflammatory drugs.
>
> Two down here stand out; visual acuity that was reduced, 26 percent in
> the saline control and in the mid-30s to upper 30s for the
> Vitrase-treated groups. Again, remember that these people had more
> clearing so there is a good chance that the reduction in V.A. which
> had to occur after they had improved so you could see the reduction
> again, because, remember, 90 percent of these were off-chart at the
> start.
>
> The vitreous-hemorrhage rebleed follows in that same vein, a little
> bit higher in those who received Vitrase.
>
> \[Slide.\]
>
> What can we say? I will give you some more details in a moment to
> support this. Vitrase administration is associated with inflammation.
> Iritis was frequent and was dose-dependent but it was not, for the
> most part, severe. We will show you some of that data in a moment. It
> was frequently self-limited, meaning no treatment was needed or
> managed with topical medications. It was also seen, as you saw, in the
> saline control group.
>
> It was not a cause of many serious adverse events and there is
> literature evidence to support that inflammation, in fact, may help
> clear vitreous hemorrhage. Certainly, when you look at some of our
> trends of clearance or reduction in vitreous-hemorrhage density, and
> in eyes that had also iritis, the iritis, in almost all cases,
> occurred on or before the onset of vitreous-hemorrhage density
> reduction.
>
> \[Slide.\]
>
> Let me show you some North America data. Remember, there were more
> reports there. Here are the adverse events that you saw. Here is a
> breakdown of these adverse events by mild, moderate and severe. You
> can see there is, again, a dose-dependent increase in those that were
> referred to as severe but most of them, the vast majority of them, are
> in the mild to moderate.
>
> Importantly, they were not looked at as causes of serious adverse
> events. Remember, I didn\'t show you any eyes that were discontinued
> from the study because of iritis. In terms of resolution, a vast
> majority, roughly three-fourths of them, were cleared within 30 days
> with or without topical treatment, and the rest of them followed soon
> after.
>
> \[Slide.\]
>
> Hypopyon, as you have seen in your briefing document, did occur. It
> was in only the Vitrase groups. Again, these eyes tended to not be
> hot. These eyes were eyes that were pretty easy to distinguish from an
> infectious endophthalmitis. It occurred most frequently in the
> 7.5 International Unit group. Again, as you would expect, with none
> here, this was a highly statistically significant relationship.
>
> Treatment of these, again, was managed by topical medications in the
> same way with prompt resolution as was the iritis.
>
> \[Slide.\]
>
> The last part of this, from looking at the North American data, is to
> look a little more in detail at the issue of adverse events of retinal
> detachment, 6 percent in the saline control group and up to 12 percent
> in the Vitrase-treated eyes. We looked at this carefully. If you do
> such things as look at retinal detachments over the first three months
> of study, among the groups, they are low and tend to be equal between
> saline and the others.
>
> This includes retinal detachments of all types including traction
> retinal detachments. In fact, traction retinal detachments were a
> large portion of these. I have more data to back this up if you want
> to get into it further later.
>
> \[Slide.\]
>
> In conclusion, iritis accounted for a majority of adverse-event
> reports and the concomitant findings of iritis such as injection,
> hyperemia, were the other most common associated adverse events. They
> tended to be self-limited or treated with topical medications with
> easy resolution. Iritis was not a common cause of a serious adverse
> event and did not lead to removal of eyes from the study or
> discontinuation.
>
> Similarly, with hypopyon, it was infrequent and medically treatable.
> The no-light-perception eyes was unrelated to Vitrase treatment.
>
> \[Slide.\]
>
> Retinal-detachment rates prior to vitrectomy are low. They don\'t
> appear to be Vitrase-related. The statistics back that up. Significant
> SAEs tend to occur after ninety days. Remember, this is a drug with a
> half life in the eye of up to four days.
>
> In summary, the safety profile of Vitrase supports human intravitreous
> administration of the drug for the treatment of vitreous hemorrhage.
>
> \[Slide.\]
>
> Next, I would like to call, in rotation, two of our lead clinical
> investigators for their perspective; first, Dr. Barry Kupperman.
>
> **Investigators\' Perspective**
>
> DR. KUPPERMAN: Hello. My name is Barry Kupperman. I am a paid
> consultant of ISTA and was one of the two lead national investigators,
> along with Gary Thomas, for the Phase III trials for Vitrase. I have
> no equity interest in the company.
>
> \[Slide.\]
>
> Like most retina specialists, approximately 50 percent of my patients
> have diabetic retinopathy and these patients are at greatest risk for
> vitreous hemorrhages. In evaluating patients with vitreous hemorrhage,
> I assess how much blood is in the eye, whether I can see into the eye
> well enough to diagnose and treat the underlying pathology and the
> impact on the patient\'s vision.
>
> The strength of the efficacy data from Vitrase presented today is that
> there were significant improvements in all of these endpoints. A
> patient with severe vitreous hemorrhage is likely to have to come in
> monthly for three months with ultrasounds and clinical examinations,
> and a vitrectomy follows some 80 to 90 percent of the time.
>
> Of greatest concern, as we are waiting for possible
> vitreous-hemorrhage clearance, is that the underlying pathology goes
> untreated, so nothing is stopping progression. Throughout this entire
> time, the patient\'s vision and quality of life is impaired.
>
> Additionally, our most important diagnostic tool, the B-scan
> ultrasound, frequently does not reveal the true extent of underlying
> pathology so both the patient and the physician are often literally in
> the dark.
>
> I am primarily concerned about missing macular pathologies like
> shallow macular-traction detachments or diffuse macular edema where
> delays in treatment can lead to poor visual outcomes. This watchful
> waiting period of three months followed by the vitrectomy and post-op
> recovery of vision can result in a four- to five-month span where
> patients are functionally limited.
>
> The most striking benefit of vitrase therapy is that it led to early
> significant improvement in visual acuity. As you will hear, return of
> useful vision, even one month earlier, is of great importance to the
> patient.
>
> \[Slide.\]
>
> I would like to play a tape for you of a patient who developed a
> vitreous hemorrhage in one eye, was enrolled by me in the Vitrase
> North American study Phase III study and, as it turned out, was
> treated with Vitrase at the 55 IU dose.
>
> Even though he has useful vision in his other eye, losing vision in
> one of his eyes from vitreous hemorrhage had a significant effect on
> his overall visual function.
>
> \[The tape was played for the committee.\]
>
> DR. KUPPERMAN: Dr. Thomas, the other lead investigator.
>
> DR. THOMAS: Good morning. My name is Gary Thomas, or Edgar Thomas, as
> you saw on the list. My parents judged to call me something else. I
> was one of the two lead investigators for the Phase III trial for
> Vitrase with Dr. Kupperman. I obviously am a paid consultant for ISTA
> but I have no equity interest in the company.
>
> I am a private-practice retina surgeon in the largest retina practice
> in Los Angeles. What you have seen in this patient video is a very
> typical scene of many of our patients There is currently only one true
> option for nonresolving vitreous hemorrhage and that is vitrectomy
> surgery.
>
> However, before we subject a patient to a vitrectomy, we usually wait
> about three months which is what we consider the standard of care. Why
> do we wait so long? Because vitrectomy, while certainly effective, is
> the most invasive surgery done in the field of ophthalmology and
> carries significant risk of complications including blindness,
> infection, retinal detachment, glaucoma and cataract.
>
> \[Slide.\]
>
> This previtrectomy period that we call watchful waiting is a
> complicated period for the patient and for the doctor. As you have
> heard from the patient in the video, he underwent this period for a
> period of three to four months. In that period of time, he sat home,
> unable to drive, work, go to the grocery store or anything by himself
> although, obviously, there were some things that he did try.
>
> His experiences with severe vitreous hemorrhage are not uncommon. In
> fact, in my opinion, this is closer to the rule than to the exception.
> In this watchful-waiting period of time, there is nothing that I can
> do positively for the patient other than hope that the vitreous
> hemorrhage clears and that the underlying cause of the hemorrhage does
> not progressively worsen.
>
> The watchful-waiting paradigm for managing vitreous hemorrhage has
> been used for over twenty years and, despite improvements in
> vitrectomy instrumentation and outcomes, it is still the standard of
> care. Therefore, we get the same results in watchful waiting for
> twenty years as we do now.
>
> \[Slide.\]
>
> As a practicing physician, I feel that we need an option besides
> watchful waiting because watchful waiting is simply not a treatment.
> Rather, it is the absence of treatment which delays patients from
> returning to normal life and keeps the physicians from doing what they
> are trying to do, namely treating pathology and healing patients.
>
> In my opinion, based on this data, Vitrase provides, for the first
> time, a viable option to watchful waiting for the treatment of
> vitreous hemorrhage and, while not perfect, would certainly be a
> welcome addition to our armamentarium.
>
> Thank you.
>
> \[Slide.\]
>
> DR. CHANDLER: Next is Dr. Kirk Packo to give another view of the
> impact of Vitrase on ophthalmology practice.
>
> **Impact on Clinical Practice**
>
> DR. PACKO: My name is Kirk Packo. I am a vitreoretinal surgeon in
> Chicago. I am not a paid consultant to ISTA Pharmaceuticals nor do I
> have any equity interest in the company. I am being reimbursed for my
> expenses and time here today.
>
> I was a local investigator as one of the 131 centers in the trial and,
> as mentioned, I am the Immediate Past President of the American
> Society of Retina Specialists, formerly the Vitreous Society, which is
> the largest organization of retinal specialists in the world with over
> 1700 members. This group makes up the vast majority of the army of
> physicians that deal with vitreous hemorrhage on a day-to-day basis
> here in the United States and my role is to speak as a foot soldier,
> of sorts, to that army.
>
> Vitreous hemorrhage in the office of a retinal specialist is a common
> problem and, as an alternative treatment to surgery, we simply have no
> other treatment. But we have a need for one. Currently, in clinical
> practice, we approach the problem of vitreous hemorrhage with a
> two-armed algorithm. On one arm, we observe the patient and this
> choice carries with it both patient and surgeon paranoia on missing
> macular pathology with instructions to go home, sleep with your head
> elevated and tough it out.
>
> It carries with it considerable frustration as we have seen because
> the patients wants the debilitating loss of vision cleared.
>
> The second arm is to move to vitrectomy and this carries with it the
> significant chance of ocular morbidity, particularly cataract
> formation, as well as the significant issue of cost, both financial
> and emotional cost. To be able to add a third arm to our algorithm I
> think would, indeed, be valuable.
>
> Drs. Thomas and Kupperman have explained this watchful-waiting period
> as a window of about a three-to-four-month range, and I agree with
> that. But many times, however, surgeons need to individualize this
> period to a shorter window of time. A patient\'s visual and
> occupational needs, for example, may mandate a vitrectomy even within
> two to four weeks, particularly if that patient is monocular.
>
> Over the past decade, I do believe that surgeons have been moving
> towards shorter waiting periods fostered by, perhaps, better surgical
> equipment and techniques. Indeed, even the DRVS showed that performing
> a vitrectomy at one month may have some value in Type 1 juvenile
> diabetics.
>
> I first became aware of the data on the Vitrase trial about a month
> ago. What impressed me is that Vitrase does work, not all the time,
> but it does work. When it does work, it does work quickly within that
> first one to two months. Adding a potential treatment alternative to
> surgery, to me, as a clinician, that important one to two months, I
> think, is very helpful.
>
> The problem of potential disease progression during a waiting period
> cannot be overstated. The hemorrhagic vitreous-detachment patient, for
> example, a nondiabetic with a suspected tear, was often not even
> entered into the Vitrase trial, but this represents a particularly
> worrisome patient.
>
> These patients often go to the operating room very early, within the
> first month, again out of paranoia or fear of missing a detachment or,
> at worse, will come back with a detachment. It seems to me a tragedy
> to see patients end up like this with potential visual loss if we did,
> indeed, have a pharmacologic way to clear their hemorrhage more
> quickly.
>
> The provision to the vitreoretinal community of a safe, relatively
> noninvasive and effective treatment to get a jump start on the
> clearance rate to vitreous hemorrhage would be embraced by that
> community wholeheartedly. To have the ability to diagnose and
> treatment patients quicker than the natural history would certainly be
> worth it.
>
> Knowing that I would be speaking to this group, over the past month, I
> took note of how many times I mentioned to my patients that we might
> have a FDA-approved drug to more rapidly clear their problem. I had
> that conversation ten times in the past four weeks.
>
> If I had a vitreous hemorrhage tomorrow, I believe I certainly would
> want the injection myself. I hope this committee will look upon the
> possibility of expanding our treatment algorithm with the same
> excitement as does the practicing retinal specialist.
>
> Thank you.
>
> \[Slide.\]
>
> DR. CHANDLER: For concluding remarks, Dr. Grillone will come back to
> the microphone.
>
> **Conclusions**
>
> DR. GRILLONE: Thank you.
>
> \[Slide.\]
>
> Ladies and gentlemen, we believe, today, we have presented to you data
> in two confirmatory clinical trials that a single intravitreous
> injection of 55 International Units of Vitrase provides the following
> benefits. First, and of primary importance, is the three-line
> improvement minimally in best-corrected visual acuity.
>
> Second, a significant reduction in vitreous-hemorrhage density that
> allows the physicians that you have heard before you today and
> yourselves as well to be able to see and diagnose the underlying
> pathology, to be able to treat that underlying pathology and to help
> your patients.
>
> \[Slide.\]
>
> What evidence have we provided to this end? First, you have seen that
> that early impact on improvement in best-corrected visual acuity is
> seen as early as Month 1. Again, you have heard the importance of that
> to the physicians. As well, you have seen that that improvement in
> best-corrected visual acuity is maintained through three months.
>
> As well, you have seen that the reduction in vitreous-hemorrhage
> density is also seen early, again at a time point important to you and
> other physicians, as early as one month and significant through to
> three months.
>
> \[Slide.\]
>
> What are the risk-benefit assessments that you have seen today? While
> a single intravitreous injection of a 55 IU dose of Vitrase would
> provide the first pharmaceutical treatment with an early reduction in
> hemorrhage density and an early improvement in best-corrected visual
> acuity, you have seen that there is a low risk of adverse events for
> these patients treated with Vitrase.
>
> With the exception of iritis, which you have also seen to be easily
> manageable and treatable, in some cases with topical medications if
> treatment, in fact, is necessary, we believe that we have provided you
> evidence that the benefits of Vitrase for the treatment of vitreous
> hemorrhage certainly outweigh the risks.
>
> \[Slide.\]
>
> At the beginning of Dr. Chandler\'s presentation, he presented you
> with a list of goals for a potential new pharmaceutical therapy. We
> also believe that we provided evidence to you today that Vitrase is
> safe with a low risk to treated eyes, that it speeds the hemorrhage
> clearance and restores visual function and allows therapy of the
> underlying pathology, but it does not preclude use of a vitrectomy
> later on.
>
> \[Slide.\]
>
> Today, more than 30 years since Dr. Malcomer conducted the first
> vitrectomy in humans, the only alternative to vitrectomy is no
> treatment. You have heard about the problems with no treatment.
>
> We ask that you carefully consider today for approval Vitrase for the
> treatment of vitreous hemorrhage as a new pharmaceutical therapy to
> provide an alternative to no treatment whatsoever for these patients
> to improve their visual acuity and to allow yourselves the opportunity
> to better and earlier diagnose and treat the underlying pathology that
> causes that vitreous hemorrhage.
>
> Thank you.
>
> DR. FONG: Thank you, Dr. Grillone.
>
> **Questions from the Committee**
>
> DR. FONG: At this point, we usually take questions to the sponsor for
> clarification, questions to clarify their presentation. We usually
> wait for discussion of the drug until the FDA has finished their
> presentation. At this point, are there any questions, clarifying
> questions, for the sponsor? Dr. Chew
>
> DR. CHEW: I had a question regarding the design of the study. I
> didn\'t see it in eligibility. I want to know what proportion of
> patients, since the majority of these cases are diabetics, what
> proportion had laser photocoagulation prior to their eligibility and
> was this balanced across all treatment groups.
>
> DR. GRILLONE: Dr. Chew, are you asking in general how many patients
> had laser photocoagulation
>
> DR. CHEW: In your integrated group. In general, sure.
>
> DR. GRILLONE: First, I will say that, of course, only the proportion
> who went in with PDR, which was about 70 percent of the patients,
> would even be eligible for laser photocoagulation. If you give us just
> a minute, we will call up the appropriate slide for that.
>
> DR. FONG: Dr. Grillone, while we are waiting, do you want to take the
> next question?
>
> DR. GRILLONE: I can take another question while we are looking for
> that.
>
> DR. FONG: Pat?
>
> DR. WILKINSON: The drug seems to act relatively quickly and we have
> heard about\--
>
> DR. FONG: Can you introduce yourself before you\--
>
> DR. WILKINSON: Yes; I am Pat Wilkinson from Baltimore. The drug
> appears to act relatively quickly. We have heard about these
> watchful-waiting periods. I think the average entry into the program
> was roughly after two months of waiting. I wonder if the data were
> stratified to look at relatively fresh hemorrhage compared to, let\'s
> say, hemorrhage of two or three months duration.
>
> In the application, there is a comment that the outcomes might have
> been even better if they had looked at more acute hemorrhages. So the
> question is, were the data stratified in terms of duration of
> hemorrhage prior to injection?
>
> DR. GRILLONE: The data were not prestratified in terms of duration of
> hemorrhage at study entry. When patients entered the study, the
> hemorrhage was already, on average, four months old. So, by the time
> the hemorrhage cleared, it was, in some cases, nearly six months old.
>
> To post stratify by hemorrhage duration meant that there was a
> significant cutting, of course post-stratification, and the numbers
> were too small, then, to draw any real conclusions because some of
> these patients\--because there was no limit on the duration of
> hemorrhage, the longevity of that hemorrhage, when you did a
> post-stratification cut, you had many patients who had hemorrhages
> that were many more days older than 90 days. So the numbers got to be
> too small to draw any conclusions.
>
> I have the laser-therapy slide that could be ready for Dr. Chew.
>
> \[Slide.\]
>
> What we looked at here, first of all, in the subset of patients that
> had PDR at study entry across the board for the integrated dataset
> with laser therapy conducted at Month 1, Month 2 and at Month 3. These
> are not cumulative. These are \"at.\"
>
> You can see that, as early as Month 1, because there is substantial
> clearing not in the saline group but, rather, in the doses, there is a
> higher percentage of patients who actually were able to get laser
> therapy when they were treated with Vitrase and, as well, it is the
> same for the Month-2 time point.
>
> DR. CHEW: I think I saw that in your datapack. I was looking for data
> prior to your entry into study, whether you collected that
> information.
>
> DR. GRILLONE: Oh; I\'m sorry.
>
> DR. CHEW: Whether people who had proliferative disease had already
> been diagnosed and had treatment prior to coming in. Obviously, those
> of us who treat know that that happens. Even in the middle of
> lasering, you get patients with severe hemorrhage that come in.
>
> So I want to know just a balance, whether there were prior laser, just
> in case there was a difference in your groups more than anything else.
>
> DR. GRILLONE: I\'m sorry. I understand. No; we did not that data
> collected. That was not built into the design of the study.
>
> DR. FONG: Dr. Feman and then Dr. Phillips.
>
> DR. FEMAN: I have two questions, somewhat of a surprise. Should there
> be any more information about visual function? Visual acuity is only
> one type of visual function. In most other studies, one is concerned
> about other aspects of visual function like peripheral visual fields
> and things like that.
>
> Yet, I didn\'t see anything in the packet that was supplied to us that
> addressed that question.
>
> DR. GRILLONE: The studies were not designed and did not include any
> other examination of any other visual functions.
>
> DR. FEMAN: Then I had a second question. In the Study 1 protocol,
> Vit-02, whatever its, the dosage was somewhat unexpected. There were
> three dosing regimens and, in it, one dose was ten times the
> concentration of the other. But the third was not halfway between the
> two. No information was given as to why that choice was made as to why
> not just stratifying it in half-way doses, or is that a company secret
> of some sort?
>
> DR. GRILLONE: No. I am glad to share that with you today. When the
> Phase III studies were designed, the only available data was data from
> two Phase II studies that were conducted. Those Phase II studies were
> conducted without a saline control and with the following doses; 7.5,
> which you saw in the 02 study, the North American study, as well;
> another dose, 37.5; and the third dose, 75.
>
> The information from the Phase II trials on the 37.5 suggested that
> there was efficacy with 37.5. However, the information on the 75 IU
> dose group in the Phase II trials also suggested that there might be a
> safety issue in the amount of inflammation and hypopyon at the 75 IU
> dose group.
>
> It was, actually, at the suggestion of Dr. Chambers, and we thank him
> for that, that we approached the 55 IU dose group to try to dose below
> the safety issues in the 75 IU dose group and yet achieve efficacy.
> That is why these two are the only studies done with the 55 IU dose
> group.
>
> DR. FONG: Thank you.
>
> Dr. Dunbar and then Dr. Steidl and Dr. Phillips, and then Dr. Tan. Dr.
> Dunbar?
>
> DR. DUNBAR: You mentioned that the illumination was not controlled
> when visual acuity was checked. I wondered if there was a consistent
> protocol throughout all the study centers for checking visual acuity
> since, initially, the study was designed with a surrogate endpoint
> that was different from visual acuity.
>
> DR. GRILLONE: I think, perhaps, I will let Dr. Chandler answer that
> and speak to the best-corrected visual-acuity measurements.
>
> DR. CHANDLER: The reference\--it was probably said fast. There was not
> strict criteria and information for off-chart in terms of
> illumination. The on-chart was done like the diabetic retinopathy
> vitrectomy study and other diabetic retinopathy studies. That was
> controlled.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: I think I have two questions. First of all, the surrogate
> success, and correct me if I am wrong, it is stated here that it was
> the primary efficacy endpoint. I was just curious, reading through
> these three bulletpoints, the first one laser treatment of the
> underlying condition completed. That makes sense.
>
> \"The visualization of the retina revealed that surgery was
> required.\" Maybe you could explain a little bit more about that
> because a lot of times, you don\'t need to see the retina to know that
> surgery is required. You can see a large detachment on a B-scan or,
> given the previous pathology, you know that there is a partial
> traction detachment there and maybe some proliferative disease going
> away and then the hemorrhage happens.
>
> How do you distinguish between that and the case where it is obvious
> that they need surgery?
>
> DR. GRILLONE: I think, as you heard from one of the physicians, at
> least, the B-scans don\'t always provide the opportunity to completely
> diagnose a traction retinal detachment, for example. In some cases,
> once there was clearance of that hemorrhage following Vitrase, then
> they could see the underlying pathology and know, for example, that
> they might have to do a scleral buckle for tractional retinal
> detachment.
>
> I can have also one of the physicians further elucidate that answer if
> you wish.
>
> DR. STEIDL: If someone had a break and an obvious detachment on
> B-scan, you wouldn\'t have to wait. If someone had an obvious large
> traction detachment, not a subtle one, you would, again, probably not
> wait. If you knew that the person had maybe regressing proliferative
> disease just prior to the hemorrhage and you had seen the patient, you
> probably wouldn\'t wait then either. So I am just curious what this
> pertains to.
>
> DR. GRILLONE: If you could see the detachments prior to study entry,
> they wouldn\'t be eligible. If you couldn\'t, however, because there
> was too much blood in the eye, then they would be eligible. But you
> now would wait for the clearance to be able to see that.
>
> I will have Dr. Kupperman come up and further expand on that answer.
>
> DR. KUPPERMAN: Lisa is correct, in that sense. Again, anybody who had
> clear pathology prior to enrollment on ultrasound was excluded from
> the trial in terms of retinal detachment. That subset of patients was
> simply those that we did not diagnose any pathology based on the
> ultrasound but diagnosed significant pathology on clearance of
> vitreous hemorrhage and, once that hemorrhage was then directly
> visualized with indirect ophthalmoscopy, et cetera, and it was
> determined that, in fact, what was needed was not panorama
> photocoagulation but, in fact, a vitrectomy, then the endpoint was
> then achieved on the date that vitrectomy was done; that is, the
> outcome is on the day that we saw that clear enough to diagnose that a
> vitrectomy was necessary. The surrogate success was the date the
> vitrectomy was done. It was for that subset of patients whose
> pathology was diagnosed purely on clearing a vitreous hemorrhage that
> was undetermined by ultrasound.
>
> DR. STEIDL: So it was group where it was ambiguous as to whether they
> needed it and, then, upon clearing it, became clearer.
>
> DR. KUPPERMAN: Generally, it was either ambiguous or it was not at all
> noted on ultrasound. Surprisingly, it was not noted on ultrasound.
> Then, once direct visualization allowed a determination, the pathology
> required a vitrectomy or other surgical procedure.
>
> DR. STEIDL: Maybe you could just stay there for one second. The second
> part is a lot of times someone has a horseshoe tear and you are
> following them and you don\'t, until you really see almost 360, you
> are not sure that there is no break.
>
> For the third bullet point, you accepted 180 degrees of clearing.
> Could you explain what that means, the 180 degrees? Is it just a
> little bit at the vitreous base or\--
>
> DR. KUPPERMAN: Right. Again, the requirement was a clearance of at
> least 180 degrees. That suggested that there was a significant amount
> of clearance with the hope that we could diagnose and spot some
> underlying pathology such that we felt comfortable that there was no
> need for a surgical intervention.
>
> We, of course, were monitoring carefully. As 180 degrees was visible,
> we could determine if there were superior retinal detachments and
> breaks although, potentially, the inferior vitreous base might be
> partially obscured.
>
> DR. STEIDL: I have one more quick question.
>
> DR. FONG: Why don\'t we let some of the other members ask a question
> and we will come back to you.
>
> DR. STEIDL: Okay.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: I note from your exclusion criteria that patients with
> prior vitrectomy were not included. But if patients with other
> intraocular surgery, especially cataract surgery, were included, what
> were the percentages and were they equally stratified between the
> treatment and control groups as patients that are pseudophakic or
> aphakic may clear more quickly than a phakic patient?
>
> DR. GRILLONE: Generally, all those patients were evenly distributed
> across the treatment groups. If I understand your question, you are
> asking if the patients who were aphakic, pseudophakic or aphakic
> cleared similarly whether they were aphakic at study entry, et cetera?
>
> DR. PHILLIPS: Correct. If they were equally stratified between the
> saline or the watchful-waiting group versus your two or
> three-treatment protocols depending on the study.
>
> DR. GRILLONE: We will be able to call a slide up for you. In the
> meantime, I can take a second question while they are finding the
> slide.
>
> DR. FONG: Dr. Tan. Then I have a question, and then back to Drs.
> Steidl and Pulido.
>
> Dr. Tan?
>
> DR. TAN: I have two questions, actually. The first one is on efficacy.
> What is exactly the primary endpoint that you defined. It seems, in
> the briefing document, it is a little bit different from what was
> presented.
>
> DR. GRILLONE: The primary efficacy endpoint in the study protocol was
> a surrogate success on or prior to Month 3. However, we believe that
> the principal-efficacy and primary-efficacy endpoint is really the
> improvement in best-corrected visual acuity.
>
> DR. TAN: Thank you. I have another clarification on the side effect.
> Is there data about\--you say there are 30.9 percent of patients who
> have returned with vitreous hemorrhage for rebleed. Are there more
> detailed. Are there more detailed data regarding how severe, how this
> compared with the patients the first time, when they are first
> enrolled in the study?
>
> DR. GRILLONE: Would you mind restating that question a bit?
>
> DR. TAN: There are 30.9 percent of patients who have rebleed occurred
> when Vitrase was used. In the saline group, there are 21.5 percent. I
> just wonder what\--you say rebleed. How about the severity? Do we have
> more detailed data about the severity of this?
>
> DR. GRILLONE: Yes. I can show you that, for example, by severity,
> recurrent vitreous hemorrhage, with the slide up.
>
> \[Slide.\]
>
> This is the 02 trial, for example. There is no statistically
> significant difference for mild, moderate or severe rebleeds. You can
> see, for the mild ones, they are all running about evenly across the
> four treatment groups and, while there is a certain proportion of
> moderate hemorrhages, similarly there is no statistical difference.
> Certainly, for the severe, there is no statistically significant
> difference with a p-value of 0.26 across the four treatment groups.
> This is in the 02, or North American study.
>
> DR. TAN: Thank you.
>
> DR. GRILLONE: I can switch, also, to the cataract slide as well. I
> think I am going to let Dr. Chandler address your question, Dr.
> Phillips, about the cataract incidence.
>
> \[Slide.\]
>
> DR. CHANDLER: On this slide, this shows you the screening status, lens
> status, as they came in. Almost no eyes\--in fact, no eyes\--were
> aphakic. They were pretty evenly distributed in those that happened to
> be\--this happens to be in reduction of hemorrhage density which is a
> slide we have, but I can tell you, from looking at the whole database,
> it is almost identical. There are a few aphakic patients, very few,
> and they are evenly distributed. The rest are distributed just about
> this way between pseudophakia and phakia.
>
> The denominator is up here of the whole database.
>
> DR. BROWN: So why don\'t those numbers add up to 100 percent?
>
> DR. CHANDLER: There is missing baseline data on some people, so you
> lose that in there. This was data that was captured in ways that are
> not ideal for collecting complete data.
>
> DR. FONG: Does that answer your question, Dr. Phillips?
>
> DR. PHILLIPS: Yes.
>
> DR. FONG: I would like to ask a question. Then back to Dr. Steidl, Dr.
> Pulido and Dr. Brown.
>
> My question has to do with the presentation from Gary and Barry about
> the patients. I think they bring up a very important point that
> patients want to function better. This is also following what Dr.
> Feman said. I am curious to know whether you have done an analysis to
> look at the percentage of patients who have had improvement of vision
> of better than 20/40 because that would be a meaningful value, because
> that would be a vision that would allow patients to drive.
>
> Also, to answer that other question, also they had talked about the
> need for prevention of vitrectomy. I don\'t see, on any presentation,
> about the distribution of vitrectomy, whether vitrectomy was actually
> saved by the use of Vitrase. So two questions, actually; percentage of
> patients that had 20/40 vision or better and whether vitrectomy was
> reduced by the injection of Vitrase.
>
> DR. GRILLONE: We did not do an analysis of patients who had 20/40 or
> better. There were several reasons for that. Then I will show you the
> analyses we do have.
>
> First, of course, because 90 percent of the patients went in with
> off-chart visual acuity, there were so many that were severely unable
> to have any vision. Second, there, of course, was a proportion of
> patients in whom an improvement of best-corrected visual acuity would
> not be achievable because, perhaps, they had macular degeneration or
> other reasons for not being able to improve.
>
> Nevertheless, we did do an analysis for the proportion of patients who
> achieved 20/200 or better which would get them out of the legally
> blind category in the study eye. I would like to show you that data
> because I think that it is an important piece of information.
>
> \[Slide.\]
>
> This is the integrated dataset for those patients who had at least
> 20/200 or better, 1.2 logMAR units. You can see that, compared to
> saline, there is a highly statistically significant difference early,
> at Month 1, for these patients with more than 20 percent of the
> patients having gone from virtually no vision, off-chart vision, count
> fingers or hand motion or light perception, to having 20/200 or
> better.
>
> Again, while the 7.5 dose doesn\'t reach statistically significance,
> certainly the 55 and 75, now at 30 percent by Month 2 and, at Month 3,
> 36 percent and 35 percent, again reaching statistical significance for
> 20/200 or better.
>
> DR. FONG: Before we move off of this, I just wanted to ask whether it
> is possible to look not just at the integrated dataset but whether you
> could sort of present the data from both the U.S. and the non-U.S.,
> that we would have a feel for what the actual numbers show.
>
> DR. GRILLONE: Certainly. We can do that. In the meantime, I will
> address the vitrectomy and we will be able to show you some data on
> that just to tell you that the studies were not designed to look at a
> reduction in incidence of vitrectomy so that there was no predesign
> for that.
>
> Nevertheless, I will show you some data that will give us some
> information.
>
> \[Slide.\]
>
> This will be the same analysis, 20/200 or better, in the North
> American study again confirming what I showed you for the integrated
> dataset, that, for the three dose groups, where you have only 11
> percent in saline, you have more than 20 percent statistically
> significant early at Month 1, 30 percent and more at Month 2 for the
> two-dose groups and, as well, while not statistically significant,
> still nearly 36 percent of the patients in the 55 IU dose group now
> have better than 20/200 vision and, in the 75 IU dose group, 38
> percent of the patients reaching statistical significance in the North
> American study.
>
> In a moment, we will put up the Ex North American study as well.
>
> \[Slide.\]
>
> In the Ex North American study, the time point for 55 only at Month 2
> reaches statistical significance but, again, the percentages are very
> similar. We have more than 30 percent of the patients at Month 2 and
> 37 percent of the patients at Month 3. So the same proportion of
> patients are achieving better than 20/200 vision, or equal to 20/200
> vision.
>
> DR. FONG: Thank you.
>
> I think Dr. Steidl has a question. Before he asks, can I also ask
> whether you could, when you present the results to us, tell us whether
> these p-values have been corrected for multiplicity, for multiple
> looks for each of these results?
>
> Dr. Steidl?
>
> DR. STEIDL: Maybe we are all kind of interested in the same thing
> because, like Dr. Fong, this is a similar question. Perhaps if I knew
> how many achieved 20/40, this would answer it, but, in trying to
> determine whether I would use this on a patient, particularly since
> there is the risk of hypopyon and other things, I would like to know
> that, if I gave the Vitrase and it was successful, what the magnitude
> of the effect would be.
>
> I don\'t know if you have evaluated that in this subgroup analysis or
> something, but if you gave Vitrase and they were successful, would it
> be much more than, say, three lines, on average, compared to the
> control group when it was actually an improvement?
>
> DR. GRILLONE: I think it would be by the data that I have just
> presented to you for the better than 20/200 because the three-line
> improvement meant that patients only got to about 1.6 LOGmar units. So
> the 20/200, 1.0, really represents about a six-line improvement in
> best-corrected visual acuity.
>
> I think that, together with the data presented for the reduction in
> vitreous-hemorrhage density which also accounts for the fact that some
> patients are not going to be able to improve that much in visual
> acuity. It also tells you that there is a sort converging data, if you
> will, to confirm that the improvement that we see and the reduction in
> vitreous-hemorrhage density are both a benefit.
>
> DR. FONG: Thank you, Dr. Steidl. We have two more questions, Dr.
> Pulido and Dr. Brown. I was just going to suggest that perhaps we
> leave the discussions about the interpretation of the results until
> after the FDA makes their presentation. So these should be just
> questions about the clarifications of the presentation.
>
> Dr. Pulido?
>
> DR. PULIDO: Jose Pulido. I have a question. I didn\'t see any evidence
> in here of which patients were using Coumadin and did you stratify for
> the use of Coumadin. These are, obviously, very sick patients. There
> is a high morality rate. Was there any difference between the use of
> Coumadin between the patients with saline and not using saline?
>
> DR. GRILLONE: We did not evaluate that in any way.
>
> DR. PULIDO: The other question that I had is in regards to safety. The
> question is do you feel comfortable integrating the data? It appears
> that the study that had 40 percent Hispanics, Vit-02-08961X, had a
> much higher incidence of adverse events. Their retinal-detachment
> rates were much higher. They had a higher incidence of iritis and
> hypopyon as well.
>
> Is it fair to maybe say that maybe people with more pigment, people of
> color, might have a higher inflammatory event with this drug than
> people that are not of color? Did you look at African-Americans to see
> if they also had a higher rate of adverse events?
>
> DR. GRILLONE: The design of the protocol did not collect the
> proportion of patients except in that category \"other\" and if the
> physician wrote in Hispanic or African American. So there wasn\'t an
> absolute check box for that category. There was the black category,
> but we didn\'t stratify in any analyses. In order to answer your
> hypothetical question about iris color, I will let Dr. Chandler come
> to the microphone.
>
> DR. CHANDLER: The comment you raised, obviously, had peaked my
> interest many times while looking at the safety data. The 7.3, without
> a companion piece from Ex North America, gives you the biggest
> proportion undiluted when you look at the integrated data of patients
> of Hispanic background.
>
> I think one of the interpretations that is reasonable is exactly that.
> The other is that a lot\--remember how many of these iritis events
> were mild and against a brown iris, sometimes, it is hard to tell red
> blood cells that have leached forward from breaking up of a hemorrhage
> from white blood cells.
>
> There are a number of things in my mind that may account for that in
> terms of looking at just overall, from a clinical evaluation. Cells
> flare. They look quite similar across the board. So maybe there is
> more reporting. I don\'t know. Remember, they had a longer follow up
> by about fifty days in that group that show up with 7.5.
>
> In terms of severity, going up with dose, actually, the 7.5, I think,
> only had one or two hypopyon patients that got higher. Those we have
> looked at in detail. They were not limited to people in the \"other\"
> category or Hispanic. They were represented, but it wasn\'t an
> exclusive event.
>
> DR. FONG: Does that answer your question, Dr. Pulido?
>
> DR. PULIDO: We can take this up later.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: I also had a question concerning the safety analysis. In
> the retinal-detachment rate, because these patients were followed for
> approximately a year and all of the incidences of these events were
> accumulated, some of those patients would have had interventions
> during that year. Others would not. Do we have a feeling for what the
> rate was in patients who did have vitrectomy versus did not have
> vitrectomy? Were they traction detachments? Any more information?
>
> DR. CHANDLER: We have two slides that will illustrate and highlight
> that for you.
>
> \[Slide.\]
>
> Here is a breakdown across treatment arms of saline in the three doses
> for the type of detachment. You get down, importantly, rhegmatogenous
> was very low, traction, relatively speaking, when it was recorded.
> Now, these are pieces of information that are picked up in various
> ways off the case-report form. There were a few, as you can see, three
> that were listed as a combination traction rhegmatogenous detachment.
>
> Again, keep in mind that there was more clearing for these people to
> have a chance to have these detected.
>
> If I can back up a little bit to a comment, those that didn\'t clear
> on visits were scheduled and had B-scan ultrasounds so that they could
> be taken out and have their vitrectomy and whatever else they needed
> if required.
>
> What you saw were those that cleared and you could reach the
> determination they needed treatment as an efficacy endpoint.
>
> If I can have the vitrectomy slide.
>
> \[Slide.\]
>
> Here are, at the top, again, with integrated dataset, the retinal
> detachments. Here were those that had a retinal detachment and
> vitrectomy, those that had a retinal detachment after vitrectomy. You
> can see it way down. And retinal detachment prior to vitrectomy, very
> low among the groups.
>
> So there is more, in general, or at least half that had their
> vitrectomy and then their retinal detachment. If you look at these in
> terms of time, most of the retinal detachments occurred after the
> Month 3 date. They were greatly delayed.
>
> \[Slide.\]
>
> Let me show you this graphically with bar graphs. For all groups, you
> can see that it stays under 2 percent and very low relatively, except
> for this early clearing group that got a chance to have detection in
> that early time period for 55. Then it balances out.
>
> But there doesn\'t appear to be an early relationship in these first
> two or three months directly to Vitrase except the clearing issue that
> they can see it.
>
> DR. FONG: Does that answer your question, Dr. Brown?
>
> DR. BROWN: Yes; it does. But the one thing which would be helpful and
> maybe we could get this for after lunch or something, but, since the
> retinal detachment was different in the two studies, and this was
> integrated dataset, I would love to see that same data but just in the
> two different studies. In fact, that would be very nice to see.
>
> DR. CHANDLER: Okay. We will do it.
>
> DR. FONG: Paula, do you have a question?
>
> MS. KNUDSON: Yes. Paula Knudson. I am not a physician so I may ask a
> very naive question. Forgive me. I was struck that the mean age of
> inclusion of subjects was 62 years. Yet, diabetic retinopathy, as I
> understand it, occurs in Type 1 diabetes who, I presume, are much
> younger. Was there an exclusion for younger people? What produced this
> 62 as a mean age?
>
> DR. GRILLONE: There was no exclusion except that minimum age was 18
> years of age. But I assume that you meant greater than 18 years of
> age. Nevertheless, the proportion of patients with diabetes are
> appearing in an older population.
>
> I would like to have Dr. Packo address the incidence of diabetic
> retinopathy in all these patients.
>
> DR. PACKO: I do think that is an excellent question and it is one that
> I am anxious to see this drug available for. As a clinician, when
> confronted with a juvenile diabetic with a dense vitreous hemorrhage,
> I was very reluctant to enroll that patient in this trial because I
> did not want to obligate them to an observational period of time after
> the injection of whatever. I was much more likely to move very quickly
> to vitreous surgery in that population.
>
> That is why I was stressing so much that, if there is a benefit in
> being able to clear enough so that I can see what is happening within
> that first one to two months, that is very valuable in the juvenile
> population which, as you know, is an important diabetic population in
> this country.
>
> DR. FONG: I have a question, then Dr. Chew and then Dr. Tan. My
> question has to do with the persistence and stability of visual-acuity
> gain. I think what Barry and Gary had said is that it is very
> important for patients to have useful vision that lasts.
>
> So my question is\--well, actually, you know what? Maybe I will defer
> that to the afternoon since that is not a clarification, but I will
> ask it now and then maybe I will re-ask it later. The question is, if
> you have improvement at one month and it doesn\'t persist, how does
> one justify that as being efficacy. You don\'t have to answer now
> because it is not clarification.
>
> Let me go with Dr. Chew. You had a question?
>
> DR. CHEW: I don\'t have a question.
>
> DR. FONG: Okay. Dr. Tan?
>
> DR. TAN: I have a clarification question. Do you have data on\--the
> baseline data, you have presented an improvement. Do you have the raw
> baseline data, summary statistics, for the BCVA and the hemorrhage
> density?
>
> DR. GRILLONE: We do. If I can call up one of the slides from the
> presentation, which are summary data, that shows that 90 percent of
> the patients, and we can look at this across\--
>
> \[Slide.\]
>
> This is the off-chart. 95 percent of the patients had no ability to
> read any letters on chart in the Ex North American study. 87 percent,
> or nearly 90 percent, in the North American study had no vision that
> was on-chart at the time of study entry. For the baseline reduction in
> vitreous-hemorrhage density\--
>
> \[Slide.\]
>
> In the presentation and with the slide up, we can see that the
> duration across the treatment groups, while the minimum entry criteria
> was hemorrhage duration for one month, in fact, in both studies, the
> hemorrhage duration in each of the studies was more than four months
> at the time of entry into the study.
>
> DR. FONG: Does that answer your question, Dr. Tan?
>
> DR. GRILLONE: We may have a breakdown if you want some further detail
> on this.
>
> DR. TAN: Yes; that is enough.
>
> DR. FONG: We have a question from Dr. Dunbar and then Dr. Brown.
>
> DR. DUNBAR: You clarified for Dr. Tan that the surrogate endpoint was
> the primary efficacy endpoint. I wondered if this best-corrected
> visual acuity as an endpoint, was that designed as a secondary
> endpoint or was there any prospective plan to validate the surrogate
> endpoint at the beginning of the study, or was best-corrected visual
> acuity looked at retrospectively?
>
> DR. GRILLONE: Let me clarify in this way. The surrogate endpoint, as
> the original primary efficacy endpoint, did require a validation
> protocol in order for the FDA to accept that surrogate endpoint.
>
> In the absence of adequate BCVA methodology from the Phase IIB trials,
> we were unable to complete a validation protocol that would be
> adequate, based on the information we had from the Phase IIB trials in
> order to design an endpoint looking at improvement in best-corrected
> visual acuity. The information we had at the time suggested that we
> would need more than 1,000 patients per treatment group to have
> best-corrected visual acuity as a primary endpoint.
>
> So, in the protocol, it was viewed as a principal endpoint, a
> secondary endpoint, but, nevertheless, the principal efficacy
> endpoint. It was clear that we had\--without the historical
> information, we were able to see a statistically significant
> improvement in best-corrected visual acuity in the Phase III trials.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: My question follows on that same issue. With the
> best-corrected visual acuity data, say a patient had an intervention
> in that first one or two months. How was the visual-acuity data
> handled? For that date when the decision was made, their visual acuity
> was recorded for that date and then no more? Or how was that handled?
>
> DR. GRILLONE: That is also a good question. For the analyses of
> improvement of best-corrected visual acuity, we basically censored,
> although these were on Kaplan-Meier analyses. But we did censor at the
> time of vitrectomy or rebleed the best-corrected visual acuity. So we
> took the best-corrected visual acuity prior to a vitrectomy so as not
> to have the influence, if you will, positive if it were a vitrectomy
> or negative if it were a recurrent vitreous hemorrhage on the BCVA so
> that we could look at just the improvement as it relates to Vitrase.
>
> DR. FONG: I have one more question and maybe we will take a break
> after my question if there are no other questions. Are there any more
> questions?
>
> Let me ask my question and then we will take a break. My question has
> to do with the integrated approach. Needless to say, there are two
> studies. One is North America and one is outside North America. There
> appear to be differences in the distribution of Type 1 diabetes and
> ethnicity and possibly in the vitrectomy rates. I am just wondering
> whether you had an analysis to show that these are not substantive
> differences and that it is okay to combine them.
>
> DR. GRILLONE: Actually, Dr. Fong, we do have an analysis to show that
> it is okay to combine these two. I would like to call one of the
> statisticians up to answer that question. Before I do that, I would
> like to, however, point out that the two studies were similarly
> designed. There were the same entry criteria, the same qualifications
> for patients. They were conducted exactly the same. The success
> criteria were all the same and we believe that the 55 and the 75 IU
> dose groups showed similar responses individually in the two studies
> and that it is permissible to pool the datasets.
>
> But it is important to know that they were done and conducted
> identically and according to GCP guidelines.
>
> If I may, then I will ask Mark Knowles to come to the microphone to
> answer that question about the poolability of the two studies.
>
> DR. KNOWLES: If I understood your question, you were asking about the
> poolability relative to the safety result; is that correct?
>
> DR. FONG: Efficacy.
>
> DR. KNOWLES: Oh; to the efficacy results?
>
> DR. FONG: Yes.
>
> DR. KNOWLES: We did do some analyses looking at that. Clearly, there
> are some differences between the studies and the absolute level of the
> response rates in the two studies. What we did is we looked at the
> response rate of the Vitrase groups versus saline and compared that
> between the two studies. I would like to show you the results of those
> analyses.
>
> DR. FONG: Dr. Pulido said he wanted to hear the discussion on safety
> as well.
>
> DR. KNOWLES: Okay.
>
> \[Slide.\]
>
> This slide is for the 55 versus saline group. We are comparing the
> dose effect of 55 versus saline and we are comparing that in the two
> studies. These p-values are from a so-called Breslow-Day test. We have
> done it for each of the four efficacy measurements and each of the
> three time points. So these p-value are all nonsignificant, saying
> there is no statistical evidence of a difference between the two
> studies on the efficacy endpoints.
>
> DR. FONG: Maybe Dr. Tan may want to comment. It seems like, to sort of
> determine whether the two groups can be compared, you want to sort of
> look at baseline differences. Are there significant baseline
> differences and how might they affect the poolability?
>
> DR. KNOWLES: We did not see any significant baseline differences
> between the two studies, I mean in terms of efficacy results.
>
> DR. FONG: Maybe I am not asking the question properly. Before you can
> look at efficacy, shouldn\'t you\--maybe Dr. Tan, like I said, should
> comment. Shouldn\'t one look at, to see whether the two studies are
> similar enough to be grouped together to look at an integrated summary
> of efficacy?
>
> DR. KNOWLES: Right. As far as I am aware, the only major difference
> between the two studies was the racial difference at baseline.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: What is the rationale you want to combine these two? Don\'t
> you already have\--this is two individual, independent, randomized
> trials.
>
> DR. GRILLONE: Exactly. We are just providing you the data both as
> individual studies\--we believe that each of those studies replicates
> evidence of efficacy from Vitrase but we also, to have a larger
> dataset, showed data integrated and just wanted to show for you that
> we have confirmed that it is statistically reasonable to combine the
> two studies.
>
> But we do believe, and I should make that perfectly clear, that we
> have two independent controlled clinical trials in which the results
> are duplicated.
>
> DR. TAN: Could you remind us, when was this, the time line, for the
> first and the second?
>
> DR. GRILLONE: The first study began a little bit earlier than the
> second study, about in 1998. The second study started a bit later. But
> there were fewer patients in the Ex North American study, only 556,
> because we don\'t have one dose group in that study. So then they both
> ran over basically the same period of time, both of them ending
> in\--enrollment ending in June, 2001.
>
> DR. TAN: Okay. Thank you.
>
> DR. GRILLONE: So they basically overlapped except for the very
> beginning part because the North American trial started a little bit
> earlier than the Ex North American study. It was a little easier for
> us to get trials initiated.
>
> DR. FONG: It is time for our break, so why don\'t we maybe discuss
> this further later on. We are going to take a twenty-minute break. I
> wanted to remind each of the members not to discuss the substance of
> the committee meeting today and to hold all discussions on line so
> that the transcript can be taken.
>
> So we will reconvene at 10:20.
>
> \[Break.\]
>
> DR. FONG: We are going to reconvene our discussion on Vitrase
> sponsored by ISTA Pharmaceuticals. Dr. Harris is going to make the
> presentation on behalf of the FDA.
>
> **FDA Presentation**
>
> DR. HARRIS: Good morning.
>
> \[Slide.\]
>
> I am Jennifer Harris. I was the primary reviewer for the NDA, for the
> Vitrase NDA. I am not going to repeat a lot of the information that
> the company has already given but what I would like to do is give you
> a flavor for how we looked at the data and how we came to our
> conclusions about the efficacy of the product.
>
> \[Slide.\]
>
> The first thing I want to clear up is how these endpoints were chosen,
> specifically if they are valid in this instance. I am going to talk
> about why it is important to correct for p-values because we were
> looking at so many different endpoints and how that affects the data.
>
> I am going to go on and talk about the efficacy results for the two
> Phase III trials, talk a little bit about safety and then on to the
> conclusion.
>
> \[Slide.\]
>
> First, there were three efficacy endpoints that were submitted in the
> NDA package. The first one was a proposed composite which was
> suggested by the sponsor. The second was clearance of vitreous
> hemorrhage and the third was best-corrected visual acuity.
>
> \[Slide.\]
>
> Now, the proposed composite was actually not just one endpoint, as you
> have seen. It was a combination of three different endpoints. But,
> basically, success was determined if the patients cleared sufficiently
> to facilitate the diagnosis of the underlying retinal pathology and to
> provide treatment, if necessary.
>
> \[Slide.\]
>
> The three components that made up this endpoint were, one, if laser
> treatment was completed; two, if you were able to visualize the retina
> and reveal that surgery was needed and that you did complete that
> surgery; and, three, if you were able to visualize the macula at a
> minimum of 180 degrees of the vitreous base.
>
> \[Slide.\]
>
> Now I want to talk about how we viewed these endpoints and if we felt
> as though they were valid or not. If we look at laser treatment
> completed, one of the problems we had with this was that it is really
> ill-defined. It is variable among ophthalmologists.
>
> For example, with patients with PDR, what is really a completed laser?
> Is it 1000 spots? Is it 1500 spots? Was it really defined by that
> point at which that patient stabilized? Even if we could come to a
> consensus on a completed laser, there are still many causes of
> vitreous hemorrhage that would not be amenable to laser treatment
>
> \[Slide.\]
>
> The second subcategory in this composite was visualization of the
> retina. We believe that this is potentially a clinically meaningful
> endpoint if it allows for earlier diagnosis of pathology and if the
> timing of the diagnosis actually translates into better patient
> outcomes or, in other words, if the patient at which it is diagnosed,
> if we have already missed that window of opportunity, it would make a
> difference to the patients.
>
> One problem with this is that now this patient is exposed to two
> invasive procedures. Not only do they get the intravitreal Vitrase
> injection but they will have to undergo vitrectomy.
>
> \[Slide.\]
>
> When we look at the third subcomponent in the proposed composite,
> which was visualization of the macula, again we believe that this
> could be potentially clinically meaningful, the reason being that one
> of the criteria is that the macula is clear. If the macula is clear,
> the patient should be able to see better and that is a clinically
> meaningful outcome.
>
> But what about the other 180 degrees. If you remember, this endpoint
> was based on only seeing 180 degrees of the vitreous base. While we
> agree that, if you were able to see 180 degrees and you saw a
> pathology that reasonably led to the vitreous hemorrhage, that that is
> probably the underlying cause.
>
> But it does not negate the fact that there could still be
> sight-threatening pathology in the other 180 degrees.
>
> \[Slide.\]
>
> So, if we look at the composite, overall, it is potentially useful as
> a surrogate endpoint if it can be validated as clinically meaningful.
> The interpretation may be difficult based on variability\--i.e., the
> style of practice from ophthalmologist to ophthalmologist. But you
> have to also remember that the underlying pathology in this situation
> may be missed and that patients may be exposed to two invasive
> procedures.
>
> \[Slide.\]
>
> So why do we call this a surrogate endpoint. It is a surrogate
> endpoint because surrogate endpoints, by definition, do not directly
> measure how a patient feels, functions or survives, and it is used as
> a substitute for a clinically meaningful endpoint.
>
> For instance, the FDA has used surrogate endpoints in the past in
> things like CD4 count for AIDS, cholesterol level for MI and those
> types of situations. But they have to be validated. They have to be
> validated through adequate and well-controlled trials to show that the
> intervention on the surrogate actually translates into a desired
> clinical outcome.
>
> \[Slide.\]
>
> This proposed composite was not validated. A validation plan was not
> completed by ISTA and, therefore, this endpoint was not accepted by
> the agency as a primary efficacy endpoint.
>
> \[Slide.\]
>
> Now let\'s move on to vitreous hemorrhage. The sponsor has already
> told you what the grading scale was; Grade 0 is a view of the retina
> and easily treatable to a dense hemorrhage of Grade 4 where there was
> no red reflex.
>
> \[Slide.\]
>
> In order to be defined as a success, in terms of the
> vitreous-hemorrhage density, that was very specific and the criteria
> only addressed those patients that had diabetes or vein occlusions.
> For PDR, you had to have at least six clock hours with a density of 0
> or 1. For vein occlusions, you had to have at least three clock hours
> with a density grade of 0 or 1.
>
> \[Slide.\]
>
> We are not sure what this means clinically. Also, the other problem is
> that it will impact the trial design and impacts how we actually
> review the results, number one, because it only addressed the vitreous
> hemorrhage associated with PDR or vein occlusions and it doesn\'t
> address any of the vitreous hemorrhages that are related to retinal
> tears, detachments or traumas.
>
> So, not only for this trial but in future trials, we would only be
> able to use this endpoint for patients who had diabetes or vein
> occlusions.
>
> \[Slide.\]
>
> So now we move on to improvement in best-corrected visual acuity which
> is the agency\'s acceptable and primary efficacy endpoint. It is
> defined as the doubling of the visual angle. An example of this is a
> three-step change on the ETDRS scale or going from 20/80 to 20/40, for
> example, on a vision chart.
>
> \[Slide.\]
>
> This is a universally accepted endpoint. I think most ophthalmologists
> in the room, if they had a patient who doubled their visual angle,
> they would accept that as being clinically meaningful and it is the
> gold standard for clinical trials.
>
> \[Slide.\]
>
> So now I want to go over the data. But before we can go over all the
> data in the Phase III trials, we have to get an idea of what we are
> looking at and how we are going to evaluate it and how we are going to
> decide what is actually statistically significant and what isn\'t.
>
> First of all, we have to realize that we are looking at a
> conglomeration of multiple different endpoints. First, we have three
> doses. In the Vit-02 study, all three doses were analyzed, 7.5, 55 and
> 75 units of Vitrase. There were three possible endpoints; the proposed
> composite, clearance of vitreous hemorrhage and best-corrected visual
> acuity. Then there were three different time points; Month 1, Month 2,
> Month 3.
>
> So, as we look at the data, how do we decide exactly what p-value will
> we look at to decide if any of those results were actually
> significant. The reason why we have to make some corrections is
> because the more endpoints you have, the more chance you have to win
> and it increases our probability of approving a drug that may not
> work;
>
> \[Slide.\]
>
> You have seen this grid before. This is the grid that will be used to
> look at all of the results for the Phase III trials. What p-value
> would we have to see in each one of these blocks for us to believe
> that the result is real and for us not to be deceived into believing
> that something is significant when it really isn\'t.
>
> The first correction we have to make is to go from 0.05 to 0.0459. Why
> is that? That is because the sponsor took a look at this data on four
> different occasions during the clinical trial. So, the most
> conservative way is to say, well, we could have gone any of nine
> different ways. We have three endpoints, three doses, three time
> points. So, at the very least, we should be looking at a p-value of
> 0.0051 before we believe that anything in here is significant.
>
> Or we can take the liberal approach, which we did, and we will say, we
> will just look at each endpoint individually. We will assume that the
> sponsor really only thought one dose will work, the 55 units. And then
> we will say, if it works in any of these time points, then we will
> take that.
>
> So, at the very minimum, as we go through the data, we should be
> looking at a p-value of 0.0153 so that we will not be fooled into
> believing that anything that has happened is not significant.
>
> \[Slide.\]
>
> So let\'s go on to the data that was submitted in the NDA for the
> Phase III trials. This is the graph of the cumulative percentage of
> patients achieving a three-line improvement in best-corrected visual
> acuity for the Vit-02 study, or the North American study, as you all
> have seen; saline, 7.5 units, 55 and 75 units of Vitrase, Month 1,
> Month 2, Month 3.
>
> What do we see? If you look at the 7.5 units of Vitrase, there does
> appear to be some efficacy early on, but this efficacy is no longer
> present for Month 2 or Month 3. If we look at the 55 units of Vitrase,
> it doesn\'t seem to be doing much early on Month 1. It does appear to
> have some efficacy at Month 2 and this peters out again at Month 3.
>
> If we look at the 75 units of Vitrase, it looks like there is
> something going on early on, which is encouraging, but, by Month 3,
> the results are not significant.
>
> So this is what we saw in the Vit-02 study. Since we always need
> replication to make sure that what we are seeing is valid, we looked
> at the Vit-03 study which is the Ex North American study or the
> international study.
>
> \[Slide.\]
>
> Remember, this does not have the 7.5 units of Vitrase. This only looks
> at the 55 and 75. So what did we see? Whereas before, in the Vit-02
> study, it looked as though Vitrase was doing something early on, we
> see that it doesn\'t show any statistical significance in this trial.
>
> Then if we look at the 55 units of Vitrase, again here at Month 2, it
> looks promising at Month 3. So, between the Vit-02 and Vit-03 study,
> the only results that replicated themselves was the best-corrected
> visual acuity at two months for the 55 units of Vitrase.
>
> \[Slide.\]
>
> So to put a clinical perspective on this, we said, okay, there does
> seem to be some difference at Month 2 but what does that mean for a
> patient? There is a statistical difference but are the patients really
> seeing it. So we looked at a distribution of the best-corrected visual
> acuity versus the percentage of patients.
>
> What we found is that, while there were statistical differences, there
> are still approximately half of the patients at Month 2 that have
> nonfunctional vision. What I mean by nonfunctional, I mean count
> fingers or worse vision. Only about 8 percent of so that have greater
> than or equal to 20/50, or what we were referring to earlier as the
> ability to be able to function and drive.
>
> \[Slide.\]
>
> So we looked at Vit-03 to see if that followed. Again, we see in the
> Vit-03 trials, that the results were similar, still at Month 2, there
> were still about 50 percent of patients who had nonfunctional vision.
> This is important to us because we knew that those patients would
> still have to go on to some additional procedure. Most physicians
> would not leave them there.
>
> \[Slide.\]
>
> So we went on to our second endpoint, which was the cumulative
> percentage and reduction of vitreous-hemorrhage density. We look at
> the Vit-02 study, again, the results are sporadic but, in 7.5 IU units
> of Vitrase, it shows some efficacy early, peters out in Month 2 and
> Month 3.
>
> For the 55 units, the only efficacy we see is at two months. For the
> 75 units of Vitrase, we see some efficacy early, which we were
> encouraged by, and that went away the Month 3. So, again, we looked at
> the Vit-03 study to see if it replicated.
>
> \[Slide.\]
>
> What we saw here was similar to what we saw in best-corrected visual
> acuity. The 75 units of Vitrase now shows no efficacy at Month 1,
> Month 2 and Month 3 and the only result that replicates itself in both
> of the trials is the 55 units of Vitrase at Month 2.
>
> \[Slide.\]
>
> So then we went on to the sponsor\'s primary efficacy endpoint which
> is this proposed composite. Remember, this was the composite which
> told you whether you had enough clearing to be able to treat the
> underlying condition. What we saw in the 55 units of Vitrase and the
> 75 units of Vitrase, there was efficacy early on.
>
> This went away by Month 3 but it was consistent in the first two
> months.
>
> \[Slide.\]
>
> So we wanted to look at Vit-03 just to make sure that it replicated
> itself and this was a real event. When we looked at the Vit-03 study,
> we found that there was no efficacy seen for either the 55 units of
> Vitrase or the 75 units of Vitrase at Month 1, Month 2 or Month 3.
>
> \[Slide.\]
>
> Since we had so many results and they seemed so sporadic to us and we
> really couldn\'t get a handle on what was going on and how do you
> really evaluate this data, we looked at a couple of other things to
> see if this could give us insight into what the problems could have
> been or what we would need to design future trials.
>
> What we found is, despite the fact that these patients were enrolled
> in a trial for a drug that was being evaluated to treat vitreous
> hemorrhage, there were still approximately a quarter of the patients
> in each treatment group who underwent a vitrectomy. So these were
> patients who the physicians felt as though they were doing bad enough
> that they would need a vitrectomy within the first three months.
>
> Then that just brought in the question, and it is up for discussion,
> does that mean that when we look at our efficacy results, are we
> really seeing the patients who actually did better? Are these the
> worst patients, these 35 or 30 percent of patients\--are these your
> bad players and they have been taken out of the efficacy analysis.
>
> \[Slide.\]
>
> Then we looked at the Vit-03 study and we found, again, that, while
> there is only about 10 to 15 percent who actually underwent vitrectomy
> in the first three months, it is a significant amount and it may be
> explained by the fact that this was Ex North American. So, does that
> bring into play the fact that the style of practice in America is
> different from that outside of the country.
>
> \[Slide.\]
>
> Then we looked at the amount of patients that were discontinued in the
> first three months for the Vit-02 study and we found that, within the
> first three months, there were approximately 10 percent, 10 to 13
> percent or so, patients who were discontinued for reasons other than
> getting a vitrectomy.
>
> \[Slide.\]
>
> In the Vit-03 study, there were about 5 to 8 percent that were
> discontinued. So, in essence, when we look at these two, when we look
> at amount of patients who had a vitrectomy within the first three
> months, the amount of patients that were discontinued in the first
> three months, what we realized is that we have lost about 25 to
> 30 percent of the patients in the efficacy analysis.
>
> So what does this mean for these results, not even these results, but
> in future trials, if we really need to run these trials to find out if
> the drug will work or not. What do we do with the fact that we are
> going to lose 30 percent of the patients in the first three months?
>
> \[Slide.\]
>
> Another thing that was curious to us was the fact that we had such a
> high death rate. In ophthalmology trials, we aren\'t used to people
> dying, or used to death rates in the 0.01 percent range.
>
> When we saw that in the Vit-02 study and Vit-03 study, that there was
> a death rate of 5 percent in each study, it was of concern to us. But
> then, more and more, we looked at the data and we realized that, based
> on the population, they were an older population, they had bad, bad
> diabetes and the major causes of death were cardiovascular, like MI,
> embolus and stroke.
>
> So we feel as though this was pretty consistent with the population
> and had nothing to do with Vitrase.
>
> \[Slide.\]
>
> Just a little bit about safety. The sponsor has given you data on the
> safety. We agree that they are similar events seen in all treatment
> groups and most of the events that are seen, we believe, are related
> to intraocular injection and not to the drug, itself.
>
> \[Slide.\]
>
> However, there are two that we do believe are drug related and that is
> the fact that there is an increased risk of dose-dependent sterile
> hypopyon and there is an increased risk of dose-dependent iritis. One
> thing that we were happy to see is that all of the sterile hypopyon
> appeared to clear with topical steroids and cycloplegics.
>
> \[Slide.\]
>
> So, the conclusion that we came up with from the study for the
> efficacy was that the only efficacy that we saw for Vitrase was the
> fact that there was an improvement in best-corrected visual acuity at
> two months and there was an improvement in the clearance of vitreous
> hemorrhage at two months. But this efficacy was no longer present at
> three months.
>
> Just to put a clinical spin on it again, while statistically it looked
> better at two months, 50 percent of those patients still have
> nonfunctional vision.
>
> \[Slide.\]
>
> Based on all that has been presented to you today, we would like the
> advisory committee to take all that information and to answer these
> questions for us.
>
> Has sufficient evidence been submitted to support the efficacy of
> Vitrase for the treatment of vitreous hemorrhage? If not, what
> additional studies are needed to establish the efficacy of this
> product? Are additional analyses of the current data needed to
> understand the efficacy or safety of Vitrase for the treatment of
> vitreous hemorrhage? Should the potential interaction, positive and/or
> negative, of Vitrase with current treatments for vitreous hemorrhage
> be evaluated? Are there adverse experiences that are of particular
> concern for this product? Is there a concern about the death rate
> observed in these studies? Do the benefits of using Vitrase outweigh
> the risks in the treatment of vitreous hemorrhage?
>
> Thank you.
>
> DR. FONG: Thank you, Dr. Harris.
>
> **Questions from the Committee**
>
> DR. FONG: Before you go, do you want to take questions from the
> committee?
>
> DR. HARRIS: Yes.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Dr. Harris, that was a wonderful presentation. A question
> that I had asked the sponsors, I would like to ask you. Do you think,
> looking at the results of the 02 study in comparison to the 03 study,
> that there is a difference in adverse events in people of color as
> opposed to people not of color since 40 percent of the patients
> enrolled in the 02 were Hispanics and 80-plus percent of the patients
> in 03 were Caucasians and there appears to be a higher incidence of
> retinal detachments and worse hypopyon formation?
>
> DR. HARRIS: That is something that we looked at. We did not feel as
> though it raised a flag for us. Actually, I did not realize that that
> 40 percent of patients who were \"other\" were actually Hispanic. So I
> will go back and look at that data again to make sure.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: You presented the data that they have in their packet
> regarding the cumulative incidence of vitrectomy over that first three
> months. So it looked like there was about a 5 percent reduction in
> patients needing vitrectomy in the Vitrase group, 55 units at three
> months. My question, was that statistically significant, that
> difference?
>
> DR. FONG: Dr. Brown, what page are you referring to?
>
> DR. BROWN: This is Page 26 in handout, the FDA handout.
>
> DR. HARRIS: Can you repeat your question?
>
> DR. BROWN: Yes. If you look at Table 15 on Page 26, it is the last
> line in that table, so that the saline control had 24.9 percent
> vitrectomy versus the 55 International Units having 20.1 percent, and
> was that statistically significant, that difference?
>
> DR. HARRIS: No; that wasn\'t. It is still of a concern to us that so
> many patients underwent vitrectomy within the first three months.
>
> DR. CHAMBERS: This is Wiley Chambers. They are not statistically
> significant. We are not really sure what to make of it. Potentially,
> you can make the argument that there is 5 percent that is benefitting
> in this particular case. That would be good.
>
> DR. WILKINSON: But you can spin it both ways. I don\'t know if\--
>
> DR. FONG: That is Dr. Wilkinson.
>
> DR. WILKINSON: Yes; Pat Wilkinson. Sorry. You could say that the
> increased visualization of the fundus made the decision to proceed
> easier. So I think the vitrectomy outcome can be very problematic. It
> can good or it can be bad.
>
> DR. CHAMBERS: This is Wiley Chambers. We absolutely agree. The point
> we were trying to raise along there, not just for this but potentially
> for future studies, is that people are unwilling to wait for a
> particular point of time, is there any hope of ever seeing potential
> benefit from a pharmacological agent because people don\'t want to
> wait X number of months even though they knew the trial was designed,
> they knew they were supposed to be waiting that period of time, and
> that was the stated outcome, three months. People obviously felt it
> was in their patient\'s best interest not to wait that period of time.
> Do we have a chance of being able to study other agents if that is the
> typical practice pattern.
>
> We only know that the push to do vitrectomies earlier is happening
> more and more as our vitrectomy procedures are getting better and
> better.
>
> DR. FONG: More questions for the FDA, clarification questions? Emily
>
> DR. CHEW: Emily Chew. I wanted to ask this question earlier because I
> thought maybe it would be best to ask the FDA because I wasn\'t
> certain how this was done, and that was the definition of a three-line
> improvement. The majority of these patients who came in had rather
> poor vision. They were off the chart, counting finger, light
> perception, hand movement.
>
> So it wasn\'t clear to me how did, say, a hand movement or LPI or
> counting finger\--how would they achieve three-line improvement. Is
> that a whole line on the chart at one meter or was there gradation?
> They did give them one line for each of the, I think, jump from one
> place to another.
>
> So, in order to be three-line improved, you had to be coming from LP
> to be on the chart for more than a line? And then what do you do with
> counting fingers? Is that two lines? That wasn\'t certain to me and I
> want to have that clarification because, in our clinical trials in the
> past, that is a really difficult area, dealing with poor vision. I
> don\'t know what the answer is. I think there needs to be a better way
> of, perhaps, quantitating these patients.
>
> Clearly, this is a trial that needed that sort of validation of such a
> scale which I don\'t have a handle on. I know, in our trials, what we
> do is we say zero is their visual acuity and it sort of puts them at a
> disadvantage because they all have to be at zero and they have to go
> onto the chart for fifteen letters to say they have a three-line gain.
> So this is difficult and problematic.
>
> I just want to hear, and I thought maybe the FDA, whether you actually
> looked at their charts or how did they actually come up with a scale
> for that?
>
> DR. CHAMBERS: This is Wiley Chambers. We also agree, we don\'t think
> there is any one good method to use. The sponsor probably has a couple
> of slides on exactly how that was done, if you want to pull that up.
> We can also talk about it. There is not a disagreement between what
> the sponsor used and the way the agency did.
>
> There are actually a couple of different minor corrections, or
> possible different ways to go and do that. That does not change the
> results when you look at it, either of those two ways, as far a
> counting.
>
> Either I can answer it or\--Dr. Grillone, do you want to answer it?
>
> DR. GRILLONE: I can answer it, Dr. Chambers.
>
> DR. CHAMBERS: Okay.
>
> DR. GRILLONE: First let me say, before we put the slide up, that, just
> to confirm, there was difficulty for us in that because of the vision
> that the patients had. We did, just to confirm in the primary analysis
> that I showed for improvement in best-corrected visual acuity, if a
> patient started out with light perception and went then to hand
> motion, that would be one line. Then that same patient went to count
> fingers, that would be the second line.
>
> Then if that patient went to reading any letters on-chart, that would
> be the third line of improvement. That would be, then, your minimum of
> at least three lines. For that third line, then, reading any letters,
> we just assumed it was 1.6 logMAR units.
>
> In the read letters as is, if the patient read a few letters, we would
> to the calculation to determine the actual logMAR unit for reading
> those letters on-chart.
>
> Now, if I can call up the slide.
>
> \[Slide.\]
>
> I think you can see that light perception, on the left-hand side
> beginning with light perception and, on the right-hand sides, both the
> logMAR and what we used in the Vitrase study might be. This logMAR,
> for example, for hand motion at 2 feet, if you knew that that was the
> distance, and keep in mind that that was not standardized and defined
> in the protocol, but if it were, it would be three units.
>
> At count fingers, at the same distance, it would be two and then 2800,
> 1.7, 2400, 1.3, and so on. In our study, because we didn\'t
> standardize, for the first three vision categories, light perception
> had an arbitrary logMAR unit of 2, hand motion, 1.9, count fingers,
> 1.8 and then 2800 was 1.7 and so on so that moving from light
> perception to reading any letters, then, would be at one, two, three
> lines of improvement in vision.
>
> DR. CHAMBERS: This is Wiley Chambers. This we think is a more
> conservative method to go and use and we are willing to accept it.
>
> DR. PULIDO: Jose Pulido. Just a question for Dr. Harris, and that is,
> considering that the Vitrase caused definite inflammation in
> comparison to the saline, do you feel comfortable that the
> investigators checking vision were well masked as to what the patient
> was taking? Do you think it might have any effects on these things
> like light perception versus hand motions vision?
>
> DR. HARRIS: No; I don\'t think it had an impact. I think they remain
> masked and I don\'t think that they would have been able to tell which
> dose of Vitrase the patients were on.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: This is Ming Tan. I just want to ask Dr. Harris, in the
> original protocol of this trial, they specifically say they are going
> to compare, they are going to compare three time points, one month,
> two months and three months?
>
> DR. HARRIS: The original proposed primary efficacy endpoint was that
> composite endpoint at Month 1, 2 or 3.
>
> DR. TAN: How about other endpoints? Did they say that the other
> variables or other endpoints were considered secondary?
>
> DR. HARRIS: Yes; other endpoints were secondary. That was what was
> proposed by the sponsor but, because of all the issues that we had
> with that proposed endpoint, as we discussed, we never accepted that
> because the only way that we could have is if it had been validated.
> And that was not done.
>
> DR. TAN: Do they plan to do three analyses for the secondary endpoints
> at one month, two months, three months, as well?
>
> DR. HARRIS: Yes; they were going to look at all three time points.
>
> DR. TAN: That was in the original protocol?
>
> DR. HARRIS: Yes.
>
> DR. FONG: Donald Fong. I have a question. Going back to the discussion
> about the defining, giving logMAR scores to the hand motions, light
> perception and count fingers, I guess I want to hear a little bit more
> discussion about why you guys thought it was okay to accept that
> designation. I guess my question is twofold. One is it is very
> subjective in that area and, two, it is hard to ascribe a value, a
> functional value, in that low area.
>
> Somebody going from light perception to even 20/800 or even seeing a
> couple of letters on there, or a single letter, seems to me a very,
> very small functional gain. So I just wanted to hear the thoughts
> about why you thought it was conservative to accept that.
>
> DR. CHAMBERS: This is Wiley Chambers. The feeling was that, from a
> comparative perspective, going form not being able to see at all, no
> light perception to light perception, to go count fingers, to go to
> hand motion, each of those steps, we have no good way of ascertaining
> how much change that is in function, how much value that is compared
> to a visual-acuity chart.
>
> It has been postulated by other groups that they are more on
> whole-unit log units change. We have not seen other people propose
> lesser amounts. So, since it was the least amount that we have seen
> proposed by different groups, that is what we were taking. That is why
> I am saying it is the most conservative.
>
> We certainly would be interested in opinions of what the proper value
> to assign to those values are. If there are people that can help us in
> the future assign values to those, we are all ears.
>
> DR. FONG: Donald Fong. Just a follow up. I think the 5/200 sort of
> cutoff used in the DRS and the ETDRS was thought by the investigators,
> at that point, and correct me if I am wrong. It is a little bit before
> my time, so I would like to hear from the more senior investigators
> what the thinking was. But my sort of secondary recollection of that
> was that was thought to be sort of the last useful amount of vision,
> so anything less than that, it seems like wouldn\'t have any
> functional value.
>
> But I am curious to hear what the other committee members think.
>
> DR. FEMAN: I can address part of that since I was involved in one of
> those studies even though I was probably the youngest man in the room
> at the time. I am Steve Feman from St. Louis University. The original
> reason for using 5/200 was that if a person\'s visual was less than
> 5/200, they needed assistance in ambulation. It changed their
> functional ability to ambulate around a room or need a seeing-eye dog.
> That is what that was used as a cutoff at that time.
>
> DR. FONG: Donald Fong, again. Then Dr. Dunbar. In follow up to that,
> do you think vision less than that has any value\--not value,
> functional implications?
>
> DR. FEMAN: Vision less than, he obviously still has vision but not as
> functional as you would like it to be. I just don\'t know how to
> extrapolate that into a numerical value like the logMAR which is just
> what Dr. Wiley Chambers was talking about earlier.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: I have a question about safety. I notice one of the
> patients was discontinued because of elevated intraocular pressure and
> there was, perhaps, a slightly higher problem with elevated
> intraocular pressure. I wondered if there was any subgroup analysis of
> patients with a diagnosis of glaucoma or if those patients were
> excluded and if there is any reason to place warnings for these
> patients on the label.
>
> DR. HARRIS: We didn\'t do a subgroup analysis of patients with
> glaucoma. There weren\'t that many that I can remember with glaucoma.
> We could surely go back and look at that again.
>
> DR. FONG: If there are no other questions for the FDA, why don\'t we
> open it up to an open discussion\--oh; one more question. Dr. Feman?
>
> DR. FEMAN: I have one more question and it may be a different approach
> to this. But we talked about death rate, the observed death rate, and
> we talked about discontinued patient and lost-to-follow-up and serious
> adverse events. Has anyone thought to combine that data or is that not
> a statistical valid method, if one looked at a combination of
> lost-to-follow-up, serious adverse events and death rates and compared
> that in the different aspects of the trial, as a combined number?
>
> DR. CHAMBERS: This is Wiley Chambers. I think the amounts are
> relatively similar in each of the groups. All it does is drop your
> total number of observed patients. That is why it was being raised an
> issue because it makes the ultimate database for which we are making
> decisions as far as vitreous-hemorrhage visual acuity on that much
> less.
>
> But we didn\'t see real differences between groups. It is just a
> matter of it brings the overall total number down that we are making
> all decisions on.
>
> DR. FONG: How about we open it up to discussion to both the FDA and
> the sponsor at this point, questions to both. Maybe I will start off
> by asking a follow-up question with the visual acuity. What if we were
> to sort to take the conservative approach and assign zero to any
> vision that was less than one-two-hundredth, no letters read on the
> eye chart?
>
> What does that do to the analysis of the three-step gain? Dr. Grillone
> or the FDA, has that been done, looked at?
>
> DR. GRILLONE: Dr. Fong, I would like to call up a slide that evaluates
> improvement in best-corrected visual acuity to 1.0 logMAR units which,
> I believe, will answer your question because this would show, of the
> patients\--and if we could have the slide on.
>
> \[Slide.\]
>
> Of the patients who came into the study not having any vision, not
> being to read letters on-chart at the study entry. So we look here at
> the top line. Those patients with light perception, hand motion of
> count fingers, certainly the majority of patients across the study
> groups for the integrated dataset now, at Month 1\--I\'m sorry; LOGmar
> score of 1.4\--we can see that there is a statistically significant
> difference, highly statistically significant, especially for 55 and 75
> IU doses at Month 1, Month 2 and Month 3.
>
> So this is the equivalence, said another way, of being able to read 15
> letters on-chart which some have asked us about.
>
> DR. FONG: Can I ask, again, the presentation, sort of the process of,
> it is hard for me to sort of see it integrated. So I am wondering
> whether you have that broken into the U.S. and non-U.S. and then the
> follow-up question is, of these results corrected for multiplicity
> and, secondly, is that just a subgroup? Do you have it included for
> everybody?
>
> DR. GRILLONE: Let me first show you, because you asked me about 02 and
> 03\--so let me show you the North American study and Ex North American
> study for 1.4 Again, with the subgroup, however, the majority of
> patients, nearly 90 percent in the North American study who had
> off-chart vision at entry. Again, the p-values are quite statistically
> significant to the 0.001 and, in the 75 IU dose group, in fact, less
> than 0.001.
>
> For the Month 2 time point, at 55, 0.002. And for the Month 5 at 75,
> also 0.001. So we believe these to be highly statistically significant
> although we don\'t have the adjustments done. In particular, you can
> see that p-values are quite robust, if you will.
>
> \[Slide.\]
>
> If we show, then, the Ex North American trial, which we have up on the
> screen now, again, as was presented by the FDA, similarly,
> confirmation that by Month 2, we see a statistically significant
> difference.
>
> While that difference is not apparent out to Month 3, you can see that
> the trend for improvement in the 55 and 75 IU group is there.
> Approximately 40 percent of the patients are now reading on-chart.
> While the difference is not significant compared to saline, of course
> saline would not be a treatment option in the clinic. So the same
> proportion of patients are able to read 15 letters on-chart out at
> three months, that being 40 percent of the patients reading fifteen
> letters on-chart.
>
> DR. FONG: Other questions? Dr. Phillips?
>
> DR. PHILLIPS: Bill Phillips. I was wondering, since approximately a
> quarter percent of the patients in the treatment group went on
> eventually to vitrectomy within the three months. Do you have a slide
> for the various indications for the vitrectomy within that time frame?
>
> DR. GRILLONE: We don\'t have a slide for the various indications
> within that time frame. I can tell you that very few patients had
> hemorrhage clearance that then meant that there was a diagnosis of
> retinal detachment. However, that wasn\'t the only subgroup.
>
> Furthermore, I would like to add, and if I could put up the slide for
> vitrectomy by three months, because we have been talking about the
> change, and I think Dr. Chambers and Dr. Harris mentioned, that in the
> saline group, 20 percent of the patients had a vitrectomy while, in
> the 55 IU dose group, 15 percent.
>
> Yes; that is a 5 percent difference but I think another way that we
> can look at that is that that is really a 20 percent relative decrease
> in the proportion of patients who had a vitrectomy. So, for those
> patients who may be at risk, for those patients who may not be a good
> candidate for vitrectomy, that certainly is a benefit to them.
>
> This can compare to the relative increase in the proportion of
> patients who actually achieve a decrease in hemorrhage and an
> improvement in best-corrected visual acuity. Those relative increases
> fluctuate approximately between 50 upwards to 80 percent.
>
> DR. PHILLIPS: I guess one specific question, then, would be, since we
> are dealing with ischemic population, either the vein occlusions or
> the diabetics, were there patients that developed rubiosis during the
> study period that had to, then, go on to vitrectomy and laser to
> prevent or decrease the risk of neovascular glaucoma?
>
> DR. GRILLONE: I think I will ask Dr. Chandler to speak to the
> patients, especially with neovascular glaucoma and rubiosis.
>
> DR. CHANDLER: I will have the data for you in just a moment. The brief
> answer is that there is no difference across the\--this is the easiest
> to see. Let\'s show this one.
>
> \[Slide.\]
>
> Here is North America. You can see rubiosis is the third category,
> actually less than the higher doses of Vitrase. But I don\'t think
> that these are statistically meaningful across the groups.
>
> In terms of increased ocular pressure, and these are measurements that
> reported as SAEs, and similar we see it with AEs, they were felt by
> the investigator to be important.
>
> There was an earlier question about glaucoma. There were a few
> patients with glaucoma. The highest pressure that led to a serious
> adverse event was a patient with a pressure of 60 millimeters of
> mercury some fourteen days after injection in the low-dose group.
>
> It was preexisting, primarily open-angle glaucoma, and was
> subsequently managed without difficulty.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: I have a question, but, before the question, could you
> leave that slide up?
>
> DR. CHANDLER: Sure.
>
> DR. PULIDO: Those weren\'t the numbers that were in Table 16. I am
> trying to get to Table 16 quickly here.
>
> DR. CHANDLER: This is serious, Dr. Pulido. I think that the table you
> are looking at is adverse events.
>
> DR. PULIDO: Right. But retinal detachment I would still consider
> serious and the numbers are different between Table 16 and these
> numbers up here.
>
> DR. CHANDLER: One of the things I want to point out to you, if you are
> looking at tables with integrated safety data in your briefing
> document\--
>
> DR. PULIDO: This is not integrated.
>
> DR. CHANDLER: Okay; the individual. We are fine, then.
>
> DR. PULIDO: In this, saline was 5.8 percent and let\'s go to the 55
> units. It was 10.3 percent. This was number percent of patients with
> ocular adverse events reported by greater than 2 percent of patients
> in any treatment group. Retinal detachment seems to be serious. Is
> there a discrepancy?
>
> DR. CHANDLER: The difference is the opinion of the investigator at the
> time of whether this was a serious adverse event in their opinion or
> just an adverse event. Most of the traction retinal detachments were
> not given a serious adverse-event designation.
>
> DR. FONG: Dr. Gates.
>
> DR. GATES: I have one question while we are on serious adverse
> effects. On average, how long did the hypopyons last? How were they
> managed?
>
> DR. GRILLONE: We will have a slide up for that and Dr. Chandler will
> address that.
>
> DR. CHANDLER: While the slides are being called up, most of the
> hypopyon occurred two- to three-days after the injection. A vast
> majority of them were considered resolve, given a resolution date by
> the physician, within fourteen to twenty-one days.
>
> Please put this up. This will be fine.
>
> \[Slide.\]
>
> So, again, these all showed up in that very first period of time of
> follow up. These eyes, by the way, were not red and angry. These eyes
> were not particularly uncomfortable. They had some discomfort but they
> were not like a raging infectious adenophthalmitis kind of problem.
> They were treated typically with corticosteroids and cycloplegics and
> resolved.
>
> By Month 3, there was just very little inflammatory response recorded,
> not in adverse events but even in cells in flare in the clinical
> ophthalmologic examinations. So these things were not lingering. They
> were time-specific, happened, resolved rapidly.
>
> DR. FONG: This is Dr. Fong. Does that answer your question?
>
> DR. GATES: Yes.
>
> DR. FONG: Dr. Pulido and then Dr. Dunbar.
>
> DR. PULIDO: This is directed towards Dr. Chandler. Considering that I
> think you were on the paper with Howard Tessler and Depak Edward about
> inflammation in pigmented eyes being more than inflammation in
> non-pigmented eyes. Again, I am still going back to this concern of
> mine. Did you do any experimental studies in rabbits to see if there
> is more inflammation in pigmented rabbit eyes using Vitrase than in
> non-pigmented rabbit eyes?
>
> DR. CHANDLER: The first part, thank you for the attribution but,
> unfortunately, I wasn\'t on the paper. I was Depak\'s advisor. We have
> done the studies on the model to look at inflammation using Dr.
> Beldid\'s pigmented iris all the way across. To the best of my
> knowledge, and we can check with the preclinical people, I don\'t
> think we have a comparison between a non-pigmented and pigmented eye.
> Everything is a pigmented. Sorry I can\'t elucidate that for you right
> now.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: Jennifer Dunbar. I wondered about the safety of this drug
> in aphakic patients. We don\'t have any information at all and I think
> that there may be some theoretical considerations that there may be
> increased inflammation or increased pressure problems in these
> patients with this drug.
>
> DR. FONG: Can I just follow up? What kind of theoretical\--
>
> DR. DUNBAR: The sponsor mentioned in their written package that they
> sent to us that the enzyme causes very small molecular-weight
> proteins. I wondered if these could just diffuse forward and cause
> problems with trabecular meshwork. They mentioned that they suspected
> even that these small-molecular-weight proteins were causing
> inflammation that may be what is helping to decrease the vitreous
> hemorrhage and if these could diffuse forward that there could be more
> anterior-segment inflammation.
>
> DR. GRILLONE: Dr. Chandler?
>
> DR. CHANDLER: I share your hypothetical concern. As you can see, we
> did not enroll very many patients, like none, virtually, that were
> aphakic. So we simply can\'t answer that question. In theory, that is
> very possible.
>
> DR. DUNBAR: If the drug was approved, do you think that there would be
> mention in the labeling that these are not known?
>
> DR. FONG: Maybe we can talk about the labeling later on. Dr. Tan and
> then Dr. Chambers and then Dr. Phillips.
>
> DR. TAN: I just want to follow up on the data discrepancy on the
> retinal detachment incidence. I think the answer that Dr. Chandler
> gave probably is not\--causes some concern to me. Since the data for
> the analysis must have a freeze to the data at a certain time point,
> you cannot\--so the analysis, your report, should be based on one
> dataset that is fixed based on a certain time point.
>
> So you cannot be different because of a physician\'s evaluation or
> opinion. So it has to be the same dataset.
>
> DR. FONG: Can I follow up Dr. Tan\'s question? I guess there is a
> discrepancy between the numbers of retinal detachment that has been
> reported by the FDA and by the sponsor. I guess the answer that Dr.
> Chandler gave before was that some of these detachments were
> tractional in nature and were thought not to be an adverse event; is
> that correct?
>
> DR. GRILLONE: Serious adverse events.
>
> DR. FONG: Serious adverse events; is that correct?
>
> DR. GRILLONE: That\'s correct. I would like to, at this point,
> distinguish there. When we are calling them serious, we are speaking
> to the issue of the regulatory definition of a serious adverse event.
>
> DR. FONG: Dr. Chambers?
>
> DR. CHAMBERS: This is Wiley Chambers. Let me first address the
> adverse-event thing. We typically do not look at whether the
> investigators label is serious or not. We look at whether we think
> particular events are serious by the nature of the event.
>
> We would consider all retinal detachments as being serious for our
> proposes and we would never distinguish as far as what was considered
> serious and not serious. We would just look at them all and look at
> the particular events.
>
> But, to go back to an earlier point made by Dr. Pulido, let me just
> assure him that we would go through\--it is routine for us to collect
> iris color as a surrogate of some pigmentation going on within the
> eye. We will go back and take a look at adverse events based on iris
> color to see if there is any differentiation in any of the trial.
>
> We have not done that yet. We will go back and do that.
>
> DR. GRILLONE: Dr. Fong, may I add, I believe a point of clarification
> that will help answer Dr. Pulido\'s question. I have consulted with my
> team and we believe that the table that you are referring to in that
> actually includes retinal detachments from both eyes; that is, retinal
> detachments that have occurred\--and, frankly, all of the adverse
> events that are reflected in both eyes.
>
> There is another table provided in the NDA that reflects, and it is
> the data that Dr. Chandler has presented throughout. We only speak of
> the adverse events, the ocular adverse events, that occurred in the
> study eye.
>
> DR. FONG: Donald Fong. I have a general question, maybe too general to
> answer, but I would like to hear how you interpret it. This is my
> question from before which is if you can\'t show that there is a
> significant difference in those patients reaching vision of 20/40 or
> better and you can\'t show a difference in reduction of vitrectomy
> rate, what are we offering the patient? The third part of it, the gain
> that you demonstrate in the first month does not persist. So what does
> the company say this product is offering the patients?
>
> DR. GRILLONE: I would like to begin the answer to that question, or
> questions, and then, perhaps, call one of the physicians up to give
> their viewpoint. The company feels that we are offering to the
> patients the ability from a dependency on, perhaps, family members or
> other caretakers to the level that they can\'t see, for example, the
> syringe gradations to give themselves injections to be able to be
> functional in their own homes, at the very least, because we did see a
> good proportion of patients that was statistically significant in both
> studies compared to saline that could now read 20/200 or better.
>
> That is quite a benefit for those patients who, up until that point,
> were completely dependent on others just for their daily activities
> and, to some degree, for their own survival because they couldn\'t
> give themselves insulin injections.
>
> So we believe that is what we are offering to the patients if this
> drug were approved. I would like to have Dr. Packo add to that based
> on his practice.
>
> DR. PACKO: I would like take your second comment first, and that is
> the relationship to vitrectomy. If you look at the data particularly
> at one year, the incidence of vitrectomy across the board was very,
> very similar. So it is clear that Vitrase does not lower the need for
> vitrectomy in this population.
>
> I think, as a clinician, the obvious interpretation of that is that
> Vitrase does not ameliorate diabetes and diabetic retinopathy. The
> indication being sought here is this is not a treatment for diabetic
> retinopathy. What this drug appears to do, certainly and two months
> and with the dose suggested, is that it does clear the vitreous of
> hemorrhage enough to look and see what diabetic retinopathy is doing.
>
> The vitreoretinal interface changes. The bonds that are creating
> traction on the retinal surface are not, in any way, being altered by
> Vitrase. So it basically does what it is being stated to do. It is
> clearing vitreous hemorrhage. The clinician looks in and still has a
> need to potentially perform vitrectomy and perhaps may even be doing
> it earlier on because we are able to diagnose these traction
> detachments where they were, perhaps, invisible on a subtle B-scan.
>
> The issue on 20/40 vision is also interesting but, again, one has to
> address the population that makes up the majority here, and that is
> the diabetic. If you look at the DRVS, which was a similar study and
> it was a group of dense vitreous hemorrhage being randomly assigned to
> observation versus vitrectomy, there was a population of patients,
> particularly out at three years, when this was a three-year study,
> that about 25 percent of those patients did achieve 20/40 vision or
> better.
>
> This is a three-month study, not a three-year study. Still, in the
> DRVS, even at six months, there was about a 20 percent group that
> achieved 20/40 vision at six months. But, again, that is in
> vitrectomy. Vitrectomy clearance of vitreous hemorrhage is certainly
> much more complete than Vitrase clearance, at least in the short-term.
> So I think that the study was not designed nor is being suggested to
> really stratify out the 20/40 visions. There is data that is being
> presented here of 20/200 vision which, I think, does appear to have
> some statistical significance.
>
> DR. FONG: My follow up; so there is agreement that this does not
> reduce the vitrectomy rate. Is that something that is agreed upon by
> the company?
>
> DR. GRILLONE: There is a trend towards reduction in the vitrectomy
> rate, especially when you look at the 20 percent that occurs in the
> saline group versus 15 percent. It is just that the study wasn\'t
> designed to demonstrate, to a statistically significant degree\--it
> wasn\'t powered to show that difference. We are simply saying that
> there are various factors here that would determine whether or not
> getting a vitrectomy\--would determine the outcome in terms of
> vitrectomy.
>
> In some cases, that would be a good thing for those patients to get
> vitrectomy earlier because the physician could see the pathology.
> Because it wasn\'t stratified or designed that way, it is impossible
> to say it is a bad thing, necessarily.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: I don\'t care who responds to this, if anyone wants to,
> but it is curiosity. I am on Page 24 of this handout, the watchful
> waiting. So it is just an n of 18. It really seems to have quite a
> different effect compared to the saline control. I am just
> wondering\--it is hard to infer anything from that, but are we
> underestimating the effect of Vitrase? Can you extrapolate that at any
> level?
>
> DR. HARRIS: Actually, we didn\'t put much credence in the
> watchful-waiting part of the trial because there just weren\'t enough
> patients to get any information from it.
>
> DR. STEIDL: The reason I bring it up is because, in the real-life
> situation, you either observe or you treat. Observation is actually
> what is significant. We are not going to inject saline into people.
>
> DR. HARRIS: Right. But the only way that we would be able to do that
> is with higher numbers or looking at historical data.
>
> DR. FONG: Dr. Chambers, I think\--well, go ahead.
>
> DR. CHAMBERS: Just responding, back to this. There are two ways to
> look at it. One, there are all the different problems with watchful
> waiting and the bias that is involved which is the other reason why we
> think there is difficulty in making interpretations there besides the
> numbers. The other is that, if we are trying to evaluate what Vitrase
> does, per se, that it is having to be injected and having to go in and
> whether there is any mechanical disturbances or any mechanical changes
> that happen with doing any kind of intravitreal injection, even if it
> is with saline, the only way to see that is to compare against the
> saline group.
>
> I would absolutely agree, it is not the same as watchful waiting, but
> it is a better evaluation of what Vitrase, per se, is doing as a
> pharmacologic agent.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: Bill Phillips. Not that the study was directly designed
> to look at this, but, for the patients that did undergo vitrectomy,
> the treating physician, where they masked as to knowing whether or not
> that patient had had saline injection or Vitrase prior and, if not,
> did the Vitrase seem to, in any way, enhance or ease the Vitrase
> surgery?
>
> DR. GRILLONE: The answer to your first question, were they masked,
> yes; they were masked and most of them actually continued to be masked
> to all of the treatment assignments for their patients.
>
> In answer to your second question, because it wasn\'t designed into
> the protocol, there was nothing particularly to say whether or
> not\--there was no data collected on ease of doing a vitrectomy, if
> you will, or not.
>
> Dr. Phillips, we could, based on some Phase II trial data for the two
> principal investigators that are here, if you wish\--that was an
> unmasked trial, however, so I don\'t know if you want to hear on their
> anecdotal experience with ease of doing vitrectomy or not, but that
> was an unmasked, noncontrolled trial.
>
> Yes? It was masked for dose. It was not a controlled trial; sorry.
>
> DR. THOMAS: Gary Thomas. We were masked to the dose in the Phase II
> trial. So we knew the patients either go 7.5, 37.5 or 75. I have been
> a vitreoretinal surgeon for twenty-two years now. Those patients that
> ultimately came to vitrectomy, I think Barry and probably Kirk can
> shadow, these were really different eyes from the standpoint of
> vitreous. There was no, I think, difference in the vitreoretinal
> attachments to fibrovascular tissue but, certainly, the vitreous,
> itself, was almost nonexistent. These were very, very quick
> vitrectomies. Barry used the term, jokingly, that we just slurped it
> out. It just really came out very quickly. But I don\'t think we saw a
> change in the vitreoretinal attachments. I think that is probably why
> we were doing the vitrectomy. It did not release those
> surface-traction components which created recurrent hemorrhage.
>
> DR. FONG: Dr. Brown, did you have a question?
>
> DR. BROWN: Yes. Jeremiah Brown. Regarding the hypothesis that
> increased inflammation may play a role in the efficacy of the drug,
> did you do any subgroup analysis to see, in your iritis population
> versus the ones that didn\'t have iritis, did they have more rapid
> clearance or difference in the rates?
>
> DR. GRILLONE: We did, as a matter of fact, look at a subgroup analysis
> of patients who had iritis and what proportion of those patients had a
> reduction in hemorrhage density since we believe that is the direct
> relationship.
>
> Before I call Dr. Chandler to the microphone, though, I would like to
> point out that this does not implicate a cause-and-effect
> relationship. It simply gives for you a bit of information about the
> relationship between iritis and reduction in hemorrhage density.
>
> Dr. Chandler?
>
> DR. CHANDLER: If we could have the slide up.
>
> \[Slide.\]
>
> What I am showing you here is iritis related to the reduction in
> hemorrhage density which, I think, gets at the question you are
> asking. In the patients with iritis, here are the numbers. Here are
> the numbers that had reduction in vitreous-hemorrhage density, again
> by treatment groups. If you look, you will see that, in all cases,
> there is a close relationship to having iritis on or prior to the date
> that reduction in vitreous-hemorrhage density was recorded.
>
> What isn\'t apparent to you here, but almost all of the iritis had its
> onset within the first few days after injection. These are, then, at
> time points after that. So they all, whether it was those that had
> iritis in the saline control or the treatment controls, had their
> iritis acutely and early in relationship to when they received their
> intravitreous injection and then here is what happened.
>
> So, if they had reduction and there was a very close correlation with
> having iritis on or prior to the day where reduction in
> vitreous-hemorrhage density occurred, or was recorded.
>
> DR. FONG: If you look at that the other way around, the ones who
> didn\'t get iritis, were the numbers lower?
>
> DR. CHANDLER: No.
>
> \[Slide.\]
>
> I will show you the other way around, sort of back into what you are
> saying. Here are, now, the patients with reduction in
> vitreous-hemorrhage density. You can look at what proportion of those,
> then, by dose group, had iritis and which proportion of those had
> iritis on or before\--had the reduction on or before the date of onset
> of the AE called iritis\--on or after; I\'m sorry.
>
> DR. FONG: Does that answer your question, Dr. Brown?
>
> DR. BROWN: Yes.
>
> DR. FONG: I have a question and then Dr. Chambers. My question to Dr.
> Chambers and to the sponsor is, if we are talking about sort of a
> temporary gain in vision or ability to see the retina, isn\'t it more
> helpful to look at the data in time and place, like a Kaplan-Meier
> sort of read on this. Is it worth cutting this down further?
>
> DR. CHAMBERS: This is Wiley Chambers. Clearly, you could do, to a set
> parameter, a Kaplan Meier and look at time to a particular event that
> you thought was useful vision. I think you are then left with a
> question, okay, how much time is clinically significant. Is it
> reduction in a day? Is it reduction in a week? Is it reduction in a
> month? I am not sure that that necessarily is as helpful in this case
> because, in most cases, you are not seeing it earlier at Month 1. You
> were seeing it, basically, at Month 2.
>
> The reoccurring finding they keep seeing is a bettering in Month 2 in
> the 55 group. I think the question, then, remains is that good, bad or
> indifferent.
>
> DR. GRILLONE: Dr. Fong, may I add to that, if Dr. Chambers is
> finished. Two things. First of all, while we are not seeing a
> statistically significant difference at Month 3, we are still seeing a
> high proportion of patients in the Vitrase-treated groups who do have
> a three-line improvement. I think it is important in the context that,
> as we have mentioned before, that patients are not likely to get
> treated with saline. That is not something we would do.
>
> So the fact remains, nevertheless, that 40 to 45 percent of the
> patients treated with Vitrase, even at three months, do have a
> three-line improvement.
>
> The second thing is, with regard to doing a Kaplan-Meier, if I may
> call up the statisticians, because we did think about this. But there
> is a statistical reason better described by the statisticians of why
> it is not appropriate to do a Kaplan-Meier in this case.
>
> DR. BUCK: Raymond Buck, Cato Research. Given the way the that data
> were collected, there are actually collected at very discrete time
> points. So a time-to-event analysis, which was more a live-table
> analysis, could be done rather than a straight Kaplan-Meier and we do
> have that if you wanted to see it.
>
> DR. FONG: If you have it, let\'s look at it. This is Donald Fong.
>
> DR. BUCK: This doesn\'t have the appearance of the usual Kaplan-Meier
> curve, but I think it shows you the survival distribution.
>
> \[Slide.\]
>
> Again, the blue line is saline, green, 7.5. Again, we are plotting the
> probability of survival rather than starting at 1 and coming down. We
> are from 0 and going up.
>
> DR. FONG: Did you test this?
>
> DR. BUCK: There were formal tests on improvement, time to BCVA
> improvement. I am not recalling the p-values exactly. I am looking at
> my colleagues now to see if they can provide you with that answer.
>
> DR. FONG: This is just a side administrative note, since we are ahead
> of schedule. I am wondering how the group thinks about taking an
> earlier lunch and reconvening earlier. Dr. Chambers?
>
> DR. CHAMBERS: This is Wiley Chambers. I think that was potentially the
> plan. We have an open public forum, meeting that it needs to more or
> less stay fairly close to being on time. So I think our expectation
> would be to go ahead and take an early lunch and then come back for
> both the open public forum as well as, then, the rest of the
> discussion.
>
> I commend the Chair for staying ahead of schedule.
>
> DR. FONG: I commend the sponsor and the FDA. Is there any opposition
> to taking an earlier lunch? Can we reconvene maybe at 12:45? An hour
> and fifteen for lunch; is that okay? Let me remind, again, the
> committee staff not to discuss the substance of this committee meeting
> outside of the transcript that is in process here.
>
> \[Whereupon, at 11:30 a.m., the proceedings were recessed to be
> resumed at 12:45 p.m.\]
>
> A F T E R N O O N P R O C E E D I N G S
>
> \[12:50 p.m.\]
>
> DR. FONG: We are going to reconvene the Subcommittee of the Ophthalmic
> Drug Advisory Committee discussing the NDA for Vitrase sponsored by
> ISTA Pharmaceuticals.
>
> **Committee Discussion**
>
> What I would like to do is have an open discussion with the sponsor
> and the FDA. Then, at 1 o\'clock, we will break for an open public
> hearing in case there are public members who want to speak up.
>
> Are there questions for the sponsor or the FDA? Dr. Brown?
>
> DR. BROWN: Just the one thing that was left over from this morning. Do
> you have that data now on the retinal detachment related to vitrectomy
> which ones had it and did not but separated between the different
> studies. So the data that was shown was the combined integrated, but
> pre- or post-vitrectomy retinal-detachment rates.
>
> DR. GRILLONE: Dr. Chandler?
>
> DR. CHANDLER: If I may have the first slide.
>
> \[Slide.\]
>
> This is the North American study showing, in the same format that you
> saw with the integrated study, total RDs. These are throughout the
> total follow up. These are not through Month 3 or anything. They are
> the total that had a retinal detachment and vitrectomy recorded.
>
> These are the portion, or the whole numbers, whatever you want of
> retinal detachment after the vitrectomy as opposed to before. I think
> you can see the numbers. It is roughly 50 percent, in each group, had
> their retinal detachment after a vitrectomy as opposed to before.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Jose Pulido. Just a point of clarification. Again, before,
> when we were talking about Table 16, you told us this was ocular
> adverse events that were\--and this is North America. But those
> numbers are exactly the numbers in Table 16. Yet, you were telling me
> that Table 16 was either eye. Is this the affected eye and are the
> numbers, then, in Table 16 of the affected eye?
>
> DR. CHANDLER: I\'m sorry; I don\'t remember what Table 16 is in your
> thing, but if it says that it is\--
>
> DR. PULIDO: It is the exact same numbers and yet you told me before it
> wasn\'t, it was either eye.
>
> DR. CHANDLER: In the integrated reports of safety in here, it is both
> eyes. In the individual studies in your document, these are study eye.
>
> DR. PULIDO: This is\--
>
> DR. CHANDLER: Study eye.
>
> DR. PULIDO: So then there were eighteen retinal detachments in the
> Vitrase-treated group with 55 International Units in the North America
> group in the study eye; correct?
>
> DR. CHANDLER: Correct.
>
> DR. PULIDO: That is 10.3 percent versus 5.8 percent for the
> saline-treated group.
>
> DR. CHANDLER: That is correct.
>
> DR. PULIDO: So, is that statistically significant?
>
> DR. CHANDLER: No; it is not.
>
> DR. PULIDO: Okay.
>
> DR. CHANDLER: Let\'s show this slide, just to give you another look at
> things.
>
> \[Slide.\]
>
> Here was time-to-diagnosis of the retinal detachments. Again, this is
> North America showing you retinal detachments in the study eye. The
> main point here is that you see very few retinal detachments reported
> as adverse events in the first month following an intravitreous
> injection. You see that it progressively increases and, as you get to
> greater than three months is where you see the bulk of them for each
> group. So they tend to be late.
>
> Would you like to see the same data for Ex North America?
>
> \[Slide.\]
>
> Here is Ex North America, giving you the same picture. Those that were
> detected in 30 days or less, 31 to 60, again 90 and greater than 90.
> Again, you will see that the majority of them tend to show up in this
> greater than 90. Here you see a good example of something cleared, in
> all likelihood, enough to make the diagnosis and then report the
> adverse event of a retinal detachment because there was clearing.
>
> DR. BROWN: That is really helpful data. I think we should get that on
> paper, the last few slides that you have shown. That is very helpful.
>
> The other part of it was traction versus rhegmatogenous and you showed
> us this morning the integrated data. Do you have that separated?
>
> DR. CHANDLER: Bear with me just a moment please.
>
> DR. FONG: Dr. Steidl has a question.
>
> DR. STEIDL: Can I just ask a question? You said what of those had
> cleared? I didn\'t follow that.
>
> DR. CHANDLER: I said, in the Vitrase-treated group, there tended to be
> clearing, as you have seen, more frequently, often uncovering a
> detachment. So you got a chance to see it earlier.
>
> DR. STEIDL: What percent would you say?
>
> DR. CHANDLER: Well, clearing in the first month went in the range of
> 25 to\--roughly 25 percent of them cleared.
>
> DR. STEIDL: Of the ones that ended up with detachments cleared enough
> to see the detachment?
>
> DR. CHANDLER: Yes.
>
> Let\'s bring up this next slide.
>
> \[Slide.\]
>
> This is Vit-02, as you have been hearing. That is North America. Here
> is the breakdown by traction, retinal detachments in this group. You
> can see that it was in this proportion, more traction retinal
> detachments, probably again a relationship to more clearing, so you
> had a better chance to see it.
>
> Here was rhegmatogenous, unspecified, since in the case reports, some
> people did not record whether it was rhegmatogenous or traction or a
> combination.
>
> DR. BROWN: That is helpful. So, then, in the interpretation of it and
> from your standpoint, you are saying that probably it helps us see it
> better. The other possibility is that the increased inflammation
> creates more traction as a possibility. Have you thought about that or
> has that been looked at in animal models or anything like that?
>
> DR. CHANDLER: We have not looked at an animal model. Certainly, we
> have thought about it. The way the numbers come over time, if it was
> looking at traction, we don\'t see a separation of this tendency in
> time between saline and Vitrase. I would think you would start to see
> those separate as you get out to three months, and we don\'t see that.
>
> DR. FONG: Dr. Feman and then Dr. Steidl.
>
> DR. CHANDLER: I didn\'t know if he wanted to also see separately the
> Ex North America or not. If you don\'t mind, Dr. Fong.
>
> \[Slide.\]
>
> Here is the 03 again, same setup. This is Ex North America traction.
> Here you see that it is pretty much straight across. Only one reported
> rhegmatogenous, and you can see a majority of them ended up
> unspecified. There was poor recording of whether it was traction,
> rhegmatogenous, combination or unspecified. But, again, I think you
> see this leaning toward that allow these were traction retinal
> detachments.
>
> DR. PULIDO: Just a point of clarification on this. If your hypothesis
> is correct that it just helps you see it better, then you would have
> had, basically\--in the two groups, it would have had the same
> numbers.
>
> DR. CHANDLER: We didn\'t have the same amount of clearing, Dr. Pulido,
> in the two studies at the same periods of time.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: My concern is about the retinal toxicity of this agent that
> you are injecting. For example, if a person has had a previous
> vitrectomy and, therefore, he does not have, or she does not have, the
> vitreous that she was born with and this agent was injected into the
> vitreous cavity, what do we know about retinal responses to this
> agent, to an eye that no longer has vitreous?
>
> DR. GRILLONE: We don\'t have any data with regard to eyes that don\'t
> have any vitreous.
>
> DR. FEMAN: There are no animal studies of any kind that would address
> this?
>
> DR. GRILLONE: Nothing in animals where we have removed the vitreous
> and then looked at retinal toxicity. I would like to have Dr. Brooks
> McCuen who is a member of our DSMB.
>
> DR. McCUEN: There really would be no indication for ever using Vitrase
> in a post-vitrectomy eye because there was no rationale for how it
> would work. The vitreous was already liquified and there is nothing to
> break up so there would be absolutely no use for using Vitrase in that
> situation.
>
> DR. FEMAN: I know that and you know that, but I don\'t know if every
> doctor in the United States would know that when this is commercially
> available.
>
> DR. FONG: It is hard to solve that problem.
>
> Dr. Steidl?
>
> DR. STEIDL: Just a protocol question. You are saying that
> three-quarters of the eye, at the time of detachment, would not have
> clearing. How are those categorized? Were those continued failures
> then, because that would not meet your primary efficacy endpoint.
>
> DR. GRILLONE: Certainly, if they didn\'t have a reduction in
> hemorrhage density, then they wouldn\'t be counted as having a
> success. But I am not quite sure that that is what Dr. Chandler was
> exactly referring to. I think he was just talking about, in a subset
> of patients, the relationship between retinal detachment and clearing.
>
> DR. STEIDL: I am just trying to understand how you are defining this
> second bullet point of the efficacy endpoints. \"Visualization of the
> retina revealed that the surgery was required.\" So, in that case, the
> surgery was required but, if you couldn\'t visualize the retina, then
> that would not be\--
>
> DR. GRILLONE: Correct. In that case, if you couldn\'t visualize the
> retina and if there was no documentation that surgery was completed,
> then that would be a treatment failure for that patient. This is where
> the distinction in the surrogate endpoint compared to the outcome by
> investigator is important because, to be a success in the surrogate
> endpoint, for that particular one, for example, we would have had to
> have had documentation on a case-report form that that surgery was
> completed within the window.
>
> On the other hand, if the physician simply checked Box No. 2 and said,
> \"Yes; the hemorrhage has cleared. I will do surgery,\" but either the
> surgery didn\'t get completed within the window or there was some
> failure to document that the surgery was done, in the outcome by
> investigator, that would be a treatment success. So those two
> endpoints are really one and the same. It is just one not requiring
> the absolute documentation. But the outcome by investigator, it is
> important to keep in mind, is really the same as a surrogate-endpoint
> success.
>
> Have I made that clear to the panel?
>
> DR. FONG: At this point, let\'s take a break in the general discussion
> and open the floor up for comments from the public.
>
> **Open Public Hearing**
>
> DR. FONG: Are there any speakers from the public who would like to
> make a comment to the committee? I don\'t see any. Does anybody see
> any? If not, let\'s resume our discussion.
>
> **Committee Discussion**
>
> DR. FONG: Maybe I will start with a question for Dr. Tan. The FDA has
> presented to us issues with multiplicity and the choice of p-value. Do
> you agree with that, that there are very few endpoints that are
> statistically significant?
>
> DR. TAN: Yes. I think I do. That is why I asked what was in the
> original protocol because the primary endpoint now were the secondary
> endpoints in the original protocol. When you make inference based on
> your efficacy on a secondary endpoint, you should really adjust it for
> the multiple comparisons. So the cutoff should be adjusted.
>
> DR. FONG: Donald Fong. You agree with the adjustment proposed by the
> FDA?
>
> DR. TAN: Yes.
>
> DR. FONG: Maybe I will just start off the discussion also again
> talking about the surrogate endpoint that has been proposed by the
> company. How do people feel about this endpoint that is proposed,
> laser treatment or visualization of the retina revealed the surgery
> was required or visualization of the macula with a 180 degrees of
> vitreous base.
>
> Observations about that? Emily
>
> DR. CHEW: I think that is a difficult one to validate. Unless it is
> validated, I think it is hard to use as an endpoint. Obviously, there
> are many issues involved that we, as clinicians every day, see. As a
> clinical trial, I think that is a difficult one. It is not
> standardized. It is not validated. People have different bars as to
> what they want to do surgery. I think that is a difficult one to
> actually use.
>
> The only hard endpoint we really have is really visual acuity at this
> point. What I would like to see, then, perhaps in that composite might
> have been some patient function aspect that might have been
> incorporated in there more than what it has got at this point. This is
> all, really, what the physician decides based on this and I think
> function has to come in there more.
>
> I think that is where I would put this.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Jose Pulido. I agree with Emily but, on the other hand, as
> one can see from the patients this was used in, this wasn\'t used in
> your Type 1 diabetics. This was used in those patients that were
> probably so sick that they couldn\'t even undergo a vitrectomy in a
> lot of cases. There is a huge mortality rate in the group of patients
> that were picked.
>
> So, thinking about whether I would use this medication or not, I think
> it would be reasonable in those patients that are so ill that I
> wouldn\'t want to take them to vitrectomy, I would want to try
> something, an alterative treatment.
>
> Although it is a bad endpoint, I think it is not an unreasonable
> endpoint to consider from a clinical point of view.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: I would agree. These patients are incredibly difficult
> to manage. It is no surprise that this is not a perfect statistical
> analysis with clean outcomes. I don\'t know. I hate to be a
> statistical nihilist, but, with all due respect to these patients, I
> think the critical issue here is that the view in is more important
> than the view out.
>
> No matter what the p-values are, it is pretty clear that, from 50
> percent to 100 percent more patients experience clearing with an
> injection than with saline, with an injection of the drug than with
> saline. So something is happening.
>
> The two things that are happening is we are getting some inflammation
> and we are getting some clearing of the vitreous gel. Don, you
> mentioned what do we offer the patient. The key to managing these
> patients is to control the retinopathy. As Dr. Harris noted, the
> amount of laser burns that a person needs to control retinopathy
> varies tremendously from many hundred to many thousand.
>
> But the key to managing these patients is to be able to see what is
> going on, what is the status of the vitreoretinal interface. I think
> if a sufficient number of people seem to be having something happen
> that can enhance their outcome that this type of surrogate analysis,
> it is not clean. It is not\--Emily stated it very, very well, but I
> think it is clinically meaningful, as Jose just said.
>
> DR. FONG: Anybody else? Observations? Dr. Tan?
>
> DR. TAN: Statistically, it comes forward here that the analysis is
> just saying if this is going to be used in a larger patient
> population, that is why I want to consider the Type 1 error.
>
> DR. FONG: Tell me that again?
>
> DR. TAN: That is the point of condidering the Type 1 error is that
> once the product is going to be used in a larger patient population,
> that is why we want to consider the Type 1 error here.
>
> DR. FONG: Maybe I can just sort of continue this ongoing discussion.
> It sounds like people like the proposed composite even though it
> hasn\'t been validated. The next issue is has the company showed that
> that has been effective, that it actually does do any clearing. What
> does Dr. Tan think of this? What do you think of the efficacy based on
> the proposed outcomes?
>
> DR. TAN: This is\--the company\--
>
> DR. FONG: Why don\'t I come back to you. Why don\'t you take a look. I
> would like to get your read on it. Other observations from committee
> members, general observations? Dr. Steidl?
>
> DR. STEIDL: Maybe I am saying the obvious but just with comment to the
> composite index, where I am having difficulty with the visualization
> of the retina as one of the endpoints is that these conditions are all
> a little different. If you suspected a peripheral break, you might
> need to see 360. That is not really included in here. Where, if you
> are suspecting vein occlusion, you may only need to see a small part
> of the eye and may only need to treat an area.
>
> So the potential, again\--some things could be managed by B-scan that
> could develop where you couldn\'t see it. So it is kind of hard for me
> to understand how you lump all these different conditions together
> with this endpoint. At the same time, I think it is valuable in
> concept.
>
> DR. FONG: This is Donald Fong, again. I sort of agree with what you
> have said and I agree with what Pat and Jose have said, and that is it
> is important\--it would be helpful to be able to see the retina to see
> if there is any pathology. But that is one step away from the
> preservation of vision or improvement of vision.
>
> What may be missing, and what Scott pointed out, is sort of the
> connection between identifying these things at one month and the
> ultimate visual prognosis. For example, if you diagnosed a detachment
> that is already there, the macula that has been off and so forth, it
> may not make a difference that you have picked this up at two months
> versus three months.
>
> So that connection may not be present. I am wondering if people agree
> with that. Thoughts on that, the connection between diagnosing things
> earlier and the ultimate visual outcome. Dr. Phillips?
>
> DR. PHILLIPS: Bill Phillips. I think some of the things, we don\'t
> really have sort of a standardized protocol in this study for the
> B-scan, but a lot of the \"traction retinal detachments,\" it is not
> broken down into whether it is macular or extramacular.
>
> Certainly, if it is a nasal extramacular detachment, you could watch
> longer than you would want to watch a macular detachment whenever you
> find it. The other thing I was a little concerned about, just as Scott
> and other people have pointed out, to say that there is clearing to
> see 180 degrees, you could missing something that way. Also saying
> that you are getting clearing enough to do \"laser treatment.\"
>
> Depending on how much ischemia there is, you may put in some laser but
> not really stop the process. If you are not stopping the ongoing
> process, you are not really treating the patient. I think what Dr.
> Feman was saying earlier, too, vitreoretinal specialists would
> probably use this in a different way than a non vitrial-retinal
> specialist and that might also lead to some sort of prolonged
> observation letting things progress further than they might otherwise
> need.
>
> DR. FONG: This is Donald Fong, again. Dr. Ringel?
>
> DR. RINGEL: I am not an ophthalmologist. I am a dermatologist. This
> question may be ophthalmologically naive but I am going to go with it
> anyway. I was wondering if there has been any stratification for
> duration of the vitreous hemorrhage. The reason I am asking is that,
> as I have listened to the committee, it seems that one would want to
> use this agent as early on as possible, perhaps at least during the
> first three months whereas, in the study population, most patients
> that had had their vitreous hemorrhage for more than three months, and
> it seems as if the study population is not the same as the population
> it is going to be used on.
>
> I would like to know if there is any stratification done specifically
> looking at safety issues.
>
> DR. FONG: Lisa?
>
> DR. GRILLONE: I will answer the last part of your question first, Dr.
> Ringel. We did not look at duration of hemorrhage as stratification
> for safety issues. For the first part, in terms of efficacy, because
> the study was not designed with a maximum limit on the duration of
> hemorrhage, it was not possible to stratify well the duration of
> hemorrhage at entry.
>
> What I mean by that is if we look at the minimum, we have 30 days. If
> we look at the mean, we have about 120 days. Nevertheless, there was a
> fair proportion of patients who actually had a hemorrhage duration
> greater than 90 days and some for quite into the hundreds of days. So,
> given that broad spectrum in this clinical trial, it is not possible
> to, then, subset duration and get meaningful information from that.
>
> DR. BULL: Jonca Bull. On this same point, the data provided by the
> sponsor has a duration of baseline vitreous hemorrhage with a mean, on
> the integrated analysis, of 120 days, about four months, for duration.
> I was just wondering how does that data address the question raised by
> Dr. Ringel?
>
> DR. GRILLONE: It has a mean of 120 days with a standard deviation of
> 110, so you could see the broad range around that. It addresses it,
> basically, by confirming that, with such a broad range\--if there were
> a tighter range around that four-month period, then you would know
> that you can get a tight subgroup analysis.
>
> But you really can\'t get a very tight subgroup analysis because the
> range goes from 30 days, in some patients, through beyond 120 days and
> beyond 230 days, based on the standard deviation, and greater. So
> there is such a broad range, the subset analysis would be
> uninterpretable.
>
> DR. BULL: I would like to point out, this raises, I think, some
> significant challenges for us from a regulatory perspective because,
> in terms of trying to write a label, you have to base it on the data.
> Given that you have patients that have fairly\--I guess, if you go
> with your mean, four months into a hemorrhage, this does not address
> whether or not you could articulate in a label any indication for
> patients, as I think someone had mentioned, who were early in the
> course, because you don\'t have data to substantiate its use.
>
> DR. GRILLONE: We didn\'t design the study to look at that small
> subset. Yes; we all agree on that but perhaps one of the physicians
> could address their feeling of how they would treat patients now based
> on the data that we have put before you if they had a patient with an
> earlier hemorrhage. What would the opportunity be for them there? Dr.
> Packo will address this.
>
> DR. BULL: Excuse me. That would be speculative. I don\'t think it is
> helpful for us to go that route.
>
> DR. GRILLONE: Okay.
>
> DR. BULL: Thank you.
>
> DR. FONG: This is Donald Fong, again. Let me come back to Dr. Tan
> about sort of the evaluation of the composite outcomes. What is your
> thinking on Vit-02 and Vit-03?
>
> DR. TAN: I think the composite score outcome is not really validated.
> I think, then, the question is can we dissect that and extract useful
> information, as you cannot take the p-value given here based on the
> composite score entirely. If you say some of the component of it is
> clinically meaningful, then we should analyze that component.
>
> DR. FONG: I am not sure I understand that. Can you rephrase it?
>
> DR. TAN: I think the composite, the outcome is not\--I think the
> correlation or how this is correlated with clinical outcome hasn\'t
> been validated. That is the issue, original issue. So, in the analysis
> of Vit-02 and Vit-03, the Vit-02 is significant but Vit-03 is not
> significant. So it is really hard to conclude, make an inference out
> of this, for me.
>
> DR. FONG: So we have one study, Vit-02, that shows some positive
> findings at Month 2 and not replicated in the third month. How do
> people feel about that? Dr. Wilkinson? Dr. Pulido? Dr. Feman? Members
> of the group?
>
> DR. WILKINSON: As I have already said, I think that there is no way to
> make this an optimal statistical study with clean outcomes. I think
> the big picture for me is that something does happen when these eyes
> are injected and it is clear to me that a patient has a significant
> chance of having some clearing of the media as well as some iritis if
> they are injected. I think that that would help me manage these
> patients.
>
> There are differences in each study. We can analyze these subsets
> until the cows come home. I am always guilty of looking at big
> pictures and not small pictures, but the bottom line is\--and this is
> the reason the first question I asked was to stratify them on the
> basis of when the hemorrhage occurred because one of the sponsor\'s
> consultants, Dr. Packo, mentioned that, for him, the first step, if
> you can\'t see an individual\'s fundus and they have a big hemorrhage,
> the question is how active is this retinopathy. What is going on? What
> do I need to do? That is the patient that is going to get this
> injection and I think the chances of clearing are better with the
> injection than with no injection.
>
> It is unfortunate that more people don\'t clear.
>
> DR. FONG: This is Donald Fong again. I just wanted to clarify, make
> sure I understand your perspective in this. What do you base the
> assertion that there is clearing on, because it is not replicated in
> this studies.
>
> DR. WILKINSON: It is my impression, just looking at these data, that
> in each and every instance, there is a 50 to 100 percent difference at
> each time period on the multiplicity of the outcomes that have been
> looked at, not always as statistically significant with one subset as
> another, but it is pretty apparent to me.
>
> Again, this is big picture, not small picture, that this drug is doing
> something. It is doing something important. It is not doing it
> optimally. I wish the number were 75 percent instead of 35 percent,
> but it seems to me that it is pretty clear something is happening.
>
> DR. FONG: Pat, let me ask this question. Sometimes, it is hard to
> tell, when you look at 100 different sorts of looks at something, and
> sort of get a gut feeling for whether something is statistically
> significant or not, or whether it is real or not.
>
> So, when you look at a bunch of things, sometimes it is hard to tell
> what is real and what is occurring just from chance. One of the
> purposes of statistical testing is to give you sort of a valuation of
> whether the findings that you are seeing is due to chance.
>
> So, if the testing doesn\'t confirm it, then I am just wondering how
> one would sort of make the assertion that there is something
> happening, I guess is what I am trying to get a feel for.
>
> DR. WILKINSON: Well, thank you. I don\'t know much about statistics,
> but I know that that is what they are for. Again, there are subsets in
> which the data\--Dr. Harris\' nice presentation pointed out, the data
> do appear to clearly support the fact that something is happening.
>
> There are other subsets in which the data are not statistically
> significant at a very, very high level. Again, I feel there is clear
> evidence here that something good is happening. These are eyes that
> have been loaded with blood for months. When we start talking about
> vision, we haven\'t talked about macular pathology in Type II
> diabetics.
>
> This is an exceptionally complicated deal. We can fine-tune it
> forever, but I cannot escape my conclusion that something is happening
> in a disappointing minority of patients, but, still, something is
> happening that is not happening in the control cases.
>
> DR. FONG: Dr. Harris, would you like to respond? Can I just follow up
> with one sort of observation? I think what Dr. Harris has shown is
> that there have been three outcomes. We looked at it with three
> different doses and you looked at it at three different times. If you
> look at things a lot of times, you are likely to find a difference
> just on chance alone.
>
> So I guess my question is how would one differentiate chance alone if
> you don\'t use statistics. I don\'t want to belabor the point. Maybe
> Dr. Tan can sort of shed some light on this.
>
> DR. TAN: That is the point. That is why you would use statistics. That
> is what the whole clinical trial is all about. You don\'t want to base
> it on, obviously, a subset of patients that the drug is working. I
> actually agree that Vitrase is doing something very good. But it is
> just not so clear. In a way, you say the control group doesn\'t do
> any\--in a way, I think, to me, from the\--I think the control group,
> the saline group, is doing something. They have the same success rate,
> but it just came one month later.
>
> They have exactly the same, or almost exactly the same, success rate
> as the Vitrase but it comes one month later.
>
> DR. FONG: So your point is that the control group came to that same
> outcome one month later
>
> DR. TAN: Right. That is consistent for the amount on the table for
> efficacy that has been presented.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: I think what we are all wrestling with is the fact that it
> is not a penicillin. It doesn\'t have a 100 percent success rate. The
> success rate is 30 percent versus 20 percent for the control. The
> statistical significance, especially after taking Bonferroni
> calculations, or whatever, becomes very, very questionable and very
> marginal.
>
> But it still appears every time to show a little bit of effect. Again,
> I harken back to\--I am concerned about the Feman factor which is the
> use of this by people that are not knowledgeable, by non-retinal
> specialists. Maybe in the labeling, we can make sure that there are
> some instructions on when to use it.
>
> But, for us that see these patients that are on Coumadin or have
> tremendous medical problems that can\'t be taken to surgery, it gives
> us at least a chance to maybe help these people.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: I just want to add that. If you look at the different ways,
> and you sort of put the question to us as to say finding out at two
> months versus three months, when is that really going to help you
> clinically. There are certain situations where we know, from the
> diabetic retinopathy study, old data, but, in certain situations, we
> certainly know that earlier treatment is better, in certain clinical
> situations.
>
> The second issue is the functional standpoint and just how does this
> patient get along in their own life. If we can increase it from being
> two out of ten to maybe three or three-and-a-half out of ten who can
> actually get back to functioning, well, that is a good thing.
>
> Then the next part of it is at what risk am I putting the others in
> that group of ten to get that one or two? From my view, the iritis and
> hypopyon seem to be easily managed without significant sequelae, no
> increased risk of neovascular glaucoma and these issues. The one thing
> that I was interested about was the retinal-detachment rate which
> appears to be higher. Whether or not we actually are inducing traction
> or is it that we are seeing it earlier. I don\'t think we know the
> answer to that.
>
> But, on the whole, I think that, to get that added benefit for those
> extra people in that group of ten, I think that the risks are
> reasonable.
>
> DR. FONG: The sponsor?
>
> DR. CRAIG: I am Dr. Craig. I am in charge of preclinical work. I
> wanted to address the Feman factor if I could, for just a second. Dr.
> Feman, you had a concern you stated about retinal damage. I didn\'t
> have a chance to jump up and talk about a primate study that we have
> done. You were addressing it specifically, I think, for where the
> vitreous had been removed and then the product injected.
>
> We haven\'t done that but we have injected the product into primate
> eyes without hemorrhage, twelve animals per arm and doses, in one arm,
> two to three times higher than the 55 IU dose and the other was four
> to six times higher. While we did see iritis, it did resolve itself as
> it has in the patients in the clinical trial.
>
> There were some effects on the retina due to the inflammation but
> there were no permanent toxicological effects on the retina.
>
> DR. FONG: Just to be the devil\'s advocate here, Dr. Brown\--this is
> Donald Fong\--I think there are two issues that this drug might be
> useful for. One is potential visual benefit to the patient leading to
> improvement in visual function and the other is improvement in the
> ability to diagnose.
>
> I am just sort of thinking aloud. I would like to hear what the other
> members think. It is hard for me to ascribe a benefit that doesn\'t
> last. So I am just going to that point first. One could argue that
> there really isn\'t a visual benefit because it doesn\'t last. I want
> to throw it out and see what people think about that.
>
> DR. WILKINSON: Don, with all due respect, I\--
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Yes; Pat Wilkinson, once again forgetting to state his
> name. I wouldn\'t expect this necessarily to improve vision. That is
> certainly not a realistic endpoint. These patients have vitreoretinal
> pathology. They all need\--the vast majority need some kind of
> treatment. Unless you spontaneously avulsed the vitreoretinal adhesion
> with some movement of the vitreous gel, you still have a traction upon
> abnormal blood vessels.
>
> There is no way that you can expect chronic permanent improvement in
> vision. This is, to my way of thinking, simply a management tool to
> allow you to differentiate a person who needs Treatment A from
> Treatment B from perhaps occasional observation.
>
> But it is a treatment tool and certainly not a cure or a means of
> improving vision directly. It is a means of improving vision
> indirectly by eliminating blindness.
>
> DR. FONG: I guess my question is, to follow up on that, is it a
> helpful tool. If the patients need a vitrectomy anyway, what have you
> gained by doing this injection. Now, this injection is not horrible.
> The risk of ophthalmitis, risk of retinal detachment is not huge, but
> it does cause a lot of pain.
>
> 60, 70 percent of the patients complained of pain, even with the
> saline injection. So this is something that patients may not tolerate.
> Now, we don\'t really have data on that right now. A lot of patients
> withdrew. 10 percent withdrew. So it is not completely a harmless
> diagnostic tool. It is an invasive procedure and if it is only
> allowing you to diagnose something one month earlier, is that helpful?
>
> DR. WILKINSON: Pat Wilkinson. I think it is exceptionally helpful. The
> one month is critical. But let me go back to my original statement.
> The critical issue here is being able to figure out where you are. We
> know from all of the ETDRS, DRVS and DRS trials that certain people
> don\'t necessarily need more laser or a vitrectomy. They can even be
> allowed to, again, become blind from the hemorrhage, assuming their
> other eye is okay. But there are others with very, very active,
> relatively new retinopathy that we know will progress like crazy, and
> certainly over a month.
>
> These people can be identified and then managed appropriately. So I
> think a transient peak is exceptionally valuable and probably the main
> reason to give this injection. I don\'t want to sound condescending
> but I think we all, sooner or later, need to ask ourselves a question,
> what if I had a proliferative diabetic retinopathy and I wasn\'t even
> at high risk but I had a massive hemorrhage. Maybe I was pagged for a
> couple of days. I\'m not clearing at all. Would I want this drug
> injected? I can assure you that, based on these data, they are not
> sensational but I am impressed that I would want the injection.
>
> DR. FONG: Comments? Dr. Pulido?
>
> DR. PULIDO: I am not sure that, necessarily, I would, especially being
> an Hispanic. The data is still questionable as far as I am concerned
> with that. But I think, again, going back to the group that I envision
> this was used in, if 25 percent die within the first year, and you
> give them one more month of vision, it is back to the time of the AIDS
> patients with CMV retinitis where we could keep their vision for a
> month, two months, three months with gancyclovir. Their quality of
> life might be a little bit better. So, because of that, I think it is
> reasonable.
>
> DR. FONG: Paula?
>
> MS. KNUDSON: I would like to ask a question. Diabetic patients would
> be at risk for the vitreous hemorrhage all the time. So you have had
> one in one eye. You have now taken care of that. You have had the
> injection and then the vitrectomy. What happens if the other eye
> becomes affected. Is this drug something that you could use again in
> the other eye? There is no contraindication to using it twice?
>
> DR. WILKINSON: No, but let me clarify. Pat Wilkinson. The major
> problem in dealing with this epidemic in our country is getting these
> individuals into the office. Someone shows up with a vitreous
> hemorrhage in one eye and they receive this injection. We hope they
> won\'t need a vitrectomy. We hope they will need laser and that is why
> this surrogate analysis was reasonable, although not clean.
>
> Once they are in the office, then we know, through these previous
> collaborative trials, who is at risk and so we hopefully can treat
> them appropriately long before they would even have any risk
> whatsoever of a hemorrhage.
>
> DR. FONG: Dr. Tan and then Dr. Pulido and Dr. Steidl.
>
> DR. TAN: I just want to\--I think Dr. Wilkinson said you would
> actually expect to see improvement of vision, but the study, the
> trial, was actually to show exactly that. So if that argument stands,
> I am having a very difficult time to interpret the data.
>
> DR. FONG: Can you elaborate what you are saying?
>
> DR. TAN: I think if Vitrase is really expected to just enhance your
> diagnosis, or make a better diagnosis instead of increasing the
> acuity, as the sponsor has presented it, the most study should be just
> on how to increase the diagnosis, the utility of this drug.
>
> DR. FONG: Can you summarize for me?
>
> DR. TAN: I think the study was designed to show improvement, you know,
> acuity; right?
>
> DR. FONG: Yes.
>
> DR. TAN: So now what I am hearing is we are not expecting this drug to
> show any improvement of acuity here. So what do we expect this drug to
> do, then? We are back to the earlier question what benefit does
> Vitrase bring to the patient. It is not clearly defined to me.
>
> DR. FONG: I think what Dr. Wilkinson has said is that what this drug
> allows the clinician to do is a temporary look at the retina and the
> pathology and the disease in the retina and then this will help guide
> as treatment. The question is\--there are two questions. From your
> standpoint, I guess, Dr. Tan, maybe is does the data support that.
>
> DR. TAN: Therefore, it is how successful this will guide you. That
> would be the information we want.
>
> DR. FONG: Let me go down the list. It was Dr. Tan, Dr. Pulido. Dr.
> Pulido?
>
> DR. PULIDO: I think Ms. Knudson\'s was actually an excellent question.
> At first thought, you would say, well, treating the second eye
> shouldn\'t have any effect. But, on the other hand, this is an
> inflammatogenic protein and it is a foreign protein. So the question
> is whether you inject in the second eye, you would increase the amount
> of inflammation. We don\'t know the answer to that. I think it is an
> excellent question.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: This is Scott Steidl. I think we all would love to have
> this thing work and be efficacious and be something that we could
> offer patients. Perhaps each of us would choose to have it done in our
> own eye. Just from the data, and I am not a statistician, it is not
> quite clear to me what it is saying.
>
> I think that these are very complicated, though. Some patients you
> suspect, wow, I really missed giving that laser treatment and now I
> can\'t see. Then there are other ones, you look at the fellow eye or
> you know the history and you really suspect maybe there is a little
> patch of peripheral neovascularization and it bled, but they can
> probably be followed.
>
> So I think it is kind of hard to generalize. So it seems to me that we
> are saying that the people that might benefit early, and it may be a
> different group. Maybe it is not a group of medical necessity but
> people who just need quicker visual resolution. They may benefit, but
> the problem is that it affects a small percentage.
>
> So if I am getting a consent, I would be saying, maybe 10 percent
> chance, but you could have eye pain, retinal detachment, inflammation.
> One thing maybe someone could address, some of the physicians that
> have used this, but, from my point of view, hypopyon is infectious
> until proven otherwise. I am nursing someone with a sterile hypopyon
> right at the moment. My blood pressure went up a bit when I saw it. I
> bit the bullet and I didn\'t inject.
>
> But I think that this is not to be minimized. I think that, in a lot
> of the literature, it is described as, oh; it is just a hypopyon and
> we will manage it. I would be curious to see what people might say
> about your constitution, seeing that many patients with it.
>
> DR. KUPPERMAN: To address the two parts of that question, first the
> issue of eye pain that has been raised a couple of times. Eye pain was
> recorded in the context of a clinical trial but, having injected this
> many times, it is the standard eye pain that is present from\--if you
> were to ask any patient after any intravitreal injection, whether that
> was gancyclovir or foscarnate in AIDS patients, triamcinolone in the
> other patients, et cetera.
>
> So this is not an exaggerated response, sir, to an intravitreal
> injection. It is the standard when you ask a patient\--we don\'t ever
> bother asking them outside of the clinical trial do they have pain. So
> it is a small amount of pain. I want to put it in that context.
>
> In terms of the hypopyon issue or the inflammation issue and how you
> react to that compared to an endophthalmitis or how do you stop
> yourself from reacting to it, because we are all trained to think
> about a hypopyon the day or two after you give an injection as
> endophthalmitis until proven otherwise.
>
> Two issues. One is that it doesn\'t look like the classic
> endophthalmitis. It is not a hot, inflamed eye. It is not massive
> injections. It is not that extraordinary pain. It doesn\'t have the
> other clinical features that go along with endophthalmitis.
>
> Secondly, by our experience, again, not one case out of all the 1500
> patients that have been injected have we seen even one case of
> injection-related endophthalmitis. There was, I think, one case that
> was two months after a vitrectomy, six months after an injection,
> something like that.
>
> DR. STEIDL: Are you approaching these patients differently than one
> that you suspect is infectious?
>
> DR. KUPPERMAN: Yes.
>
> DR. STEIDL: Fewer visits and that sort of thing?
>
> DR. KUPPERMAN: Oh, yes, because it is a consequence injection, we
> think that\--again, we know that there is iritis. Again, my patient
> population, Jose, to address some of your concerns, again, in the
> limited population has been largely Hispanic and I have not seen any
> untoward severity of inflammation in terms of manageable amounts of
> iritis after this injection. I am sensitive to that patient
> population, being a family from Brazil, as well, my own family, and
> have been sensitive to that. I have not seen an untoward amount of
> inflammation in those eyes.
>
> So, again, it is a retraining of your mind set because one does want
> to react to that as if it is an endophthalmitis but, given this known
> inflammatory consequence, it is a retraining that will need to be
> done.
>
> DR. STEIDL: I guess, just quickly, the corollary of that is if we
> downplay that, who knows. Maybe Vitrase is protective against
> endophthalmitis. I don\'t know. But if we take a more cavalier
> approach to it\--it is kind of hard to say that you can put down your
> guard. I don\'t know. Then you might\--
>
> DR. KUPPERMAN: I continue to have an index of suspicion but, again,
> without that beefy looking conj and some of the other factors that go
> along with it, there tends to be just redness at the injection site, a
> quiet otherwise looking conjunctiva and episcleral vessels, et cetera,
> and inflammation inside the eye and/or a layered hypopyon. It is a
> different picture than one would normally be concerned about with a
> classic endophthalmitis.
>
> DR. FONG: The sponsor?
>
> DR. CRAIG: Bill Craig, again. I wanted to address Ms. Knudson\'s
> question and the response to it. It is along the same lines. In that
> monkey study that I mentioned, we did have an arm that received a
> second injection of the product. As I mentioned, the first injection
> caused the type of iritis that we expected to see. Once that had
> resolved to a great degree, we did a second injection. We saw almost
> exactly the same reaction. It was certainly no worse.
>
> In fact, I was just looking over the data the other night. The
> hypopyon was reported in the first injection but, interestingly, there
> was no report of hypothesis in the second injection and it resolved as
> quickly as it did on the first injection.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: I am Steve Feman. I would like to expand on what I think
> Dr. Tan was trying to get at earlier and correct me, Dr. Tan, if I
> have misinterpreted what you have said. The impression is that, if the
> drug does not improve visual acuity which is what we all seem to be
> talking about. But its major effect is that it works to allow the
> physician to see the retina better. Is there any data in the packet
> that we have received that proves that? Is the data designed to show
> that? Is any part of the study designed to show that it allows the
> physician to see the retina better?
>
> It may be here and it is just that I may not have seen it.
>
> DR. TAN: I don\'t see it either.
>
> DR. FONG: Dr. Wilkinson? Do you have any follow up, any thoughts on
> what Dr. Feman said?
>
> DR. WILKINSON: Pat Wilkinson. I don\'t have any thoughts but I can
> reiterate what I have said. I think the surrogate analysis, the fact
> that\--I was just trying to grab Dr. Harris\' data to see if I could
> find anything there. Perhaps you would be the best person to answer,
> Dr. Harris.
>
> It just seems to me that there was 50 to 100 percent greater chance
> that the patients could be managed in some fashion if they receive the
> drug.
>
> DR. FONG: Dr. Harris?
>
> DR. HARRIS: I think you are asking about the proposed composite, that
> endpoint that says, can we see it and, from a physician\'s standpoint,
> are they able to see it and treat patients better. We need to look at
> both trials independently because we need validation from both trials
> in order to make a decision.
>
> We can\'t base all of our experience on one trial. That could just
> happen by chance. So we look to see if it has been replicated. That is
> why I presented these two charts. We looked at Vit-02 to see what it
> actually showed. I agree that, in Vit-02, it shows that there does
> seem to be some efficacy for the 55 units of Vitrase in the first two
> months.
>
> But when we look at the Vit-03 trial to see if anything replicates, it
> is a failed study. It doesn\'t show that anything replicates. So we
> base our decision on which trial? Do we base it on Vit-02 and say that
> we see something or do we base it on Vit-03 and say that there is
> nothing?
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: Bill Phillips. I just had sort of a general comment,
> too, from the actual practice standpoint. Initially, in their NDA,
> they were stating that vitreous hemorrhages are typically observed for
> six months. That was true in the past. Then some of the physicians
> that were speaking on behalf of the sponsors would say, well, we will
> typically watch a vitreous hemorrhage for three months.
>
> That is certainly possible and could fall within standard of care.
> Standard of care certainly varies from region to region. In the
> Washington, D.C. area, when you are looking at the majority of the
> patients that were enrolled in this study, all being 20/200 and worse
> and most either count fingers, hand motion or light perception, they
> would not end up waiting three months for a vitrectomy.
>
> So, if we are looking at the efficacy in the 55 International Unit
> group being at two months, we are getting a view. Very few of the
> patients in this area even would wait two months with that dense of a
> hemorrhage. So that is one thing. We are sort of comparing it. I
> understand, within the context of the study, we have to compare it
> either to watchful observation or saline.
>
> But there is also another alternative which is the vitrectomy that, in
> the real world, has to be discussed with any patients except for those
> that medically could not undergo a vitrectomy which may end up being
> the best indication for this drug. I think it would be very useful
> then.
>
> The other thing is just looking at the endpoint in the composite of it
> is clear enough that we can now see the retina to make a determination
> of treatment. If that treatment is just laser and it stays clear long
> enough that we can do that, that\'s great. But the data also shows
> that, in many cases, that determination was there is a retinal
> detachment which ended up needing the vitrectomy anyway. So you have
> now gone through two procedures, the injection and then the subsequent
> surgery.
>
> I think we have to take all those points into account in looking at
> the efficacy overall.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: I just wanted to speak to what Dr. Phillips had been
> addressing. The reason why the three-month, four-month interval has
> come to practice is that, in the original derivation of the diabetic
> retinopathy vitrectomy study, it was found that at approximately four
> months, you can start measuring electroretinographic abnormalities by
> doing bright-flash ERGs, that there was a retinal toxicity from the
> iron in the hemoglobin being present in the eye so long.
>
> That is why the time intervals have gone from six months down to three
> to four months. But I think that is where the standard is now. I
> don\'t think there are very many practitioners anywhere in the United
> States that would wait more than three months before doing a
> vitrectomy because of the danger of having retinal toxicity, of having
> the blood in the eye that long, which leads us back to this study that
> we are examining right now, when many of the eyes that were enrolled
> in the study had the blood present for 121 days, as I recall from an
> earlier slide.
>
> Correct me if I am wrong, but I thought that they said that the
> average entrance patient, the mean of the entrance patients, had blood
> in their eye for 121 days which is longer than the standard in most
> parts of the United States.
>
> DR. FONG: So what is the corollary? Is there a corollary to that, Dr.
> Feman?
>
> DR. FEMAN: Again, I just see the value of this medication other than
> as a chance of delaying a vitrectomy that the patient might need.
> Again, I have this great concern about toxicity, not necessarily from
> the drug, perhaps, but from the blood having been present in the eye
> so long.
>
> DR. FONG: At some point, we will need to take a vote on the questions.
> But it sounds like there is some more discussion. Dr. Wilkinson?
>
> DR. WILKINSON: I wanted to speak even though I don\'t disagree\--Pat
> Wilkinson, by the way\--with Dr. Feman\'s premise that, in fact, those
> of us that are old enough to have been around when vitreous surgery
> began, our best cases, we operated on even before the lie-pipe was
> invented, had had an eye full of blood for twenty years. This toxicity
> may be visible on an ERG but many of these patients did beautifully.
>
> If their macula worked well, they had an absolutely phenomenal
> outcome. So I don\'t think blood toxicity is a critical issue. I would
> agree with Dr. Phillips. I think very few people will allow
> observation for three months.
>
> But, again, if the patient\--the critical thing is the activity of
> that retinopathy. If the patient has had scatter, this is something
> Emily wanted to get into, how many eyes had already had scatter. If a
> patient has had scatter, they are at no risk for tremendous
> proliferation and they are into just some mild traction, they can be
> watched indefinitely if their other eye is okay.
>
> If they have very, very active retinopathy that has never been
> treated, then they critically need treatment immediately. So the
> concept of a preoperative management tool is, to me, the most
> appealing.
>
> DR. FONG: Dr. Chew?
>
> DR. CHEW: I just have a comment, I think, more than anything else. As
> a clinical trialist, there are a lot of shortcomings of the study.
> There is no question. I think we are having trouble trying to decide
> one way or the other. We don\'t have a good endpoint. There isn\'t a
> good endpoint here. It is a difficult situation. These are tough
> patients.
>
> As a clinical trialist, I don\'t like the trial because I think there
> are many things that we would have liked more information on. But it
> is what it is. The patients, themselves\--I think we are going to come
> down to deciding as clinicians more than as biostatisticians or
> clinicians who do clinical trials because we don\'t have that
> information in front of us that really allows us to make that
> information really in an informed way.
>
> I think a lot of it is going to boil down to what would you do as a
> clinician and how would you feel as a patient if you were in the
> situation. Then it becomes a balance of how much harm are you doing to
> these patients. How bad is this hypopyon?
>
> If you look at it, 55 IU, I think hypopyon was, in the first
> trial\--was it about 1 percent? Is that right? So it is not like it is
> an outrageous amount. We are not talking about a huge amount of
> complication. So I think a lot of this has to be really balanced on
> how we are going to\--we are looking for Dr. Tan and others to give us
> guidance. I think that is why FDA has us here because, if they knew
> they had a good statistical method, they would have it approved by
> now. They would have it approved and all finished.
>
> So I think a lot of it has to be discussed, the balance of the two, in
> terms of our practice.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: An issue I would like to bring up is that this is a novel
> therapy and the decisions about this therapy will serve as a precedent
> for other therapies in the future. Because the clinical situation is
> so grave for these patients, it is very tempting to us to lower the
> bar. However, we may be lowering the bar for many years to come and
> thus discourage even better therapies that may be just around the
> corner.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: Just a quick question for the company. Was there
> quality-of-life data obtained?
>
> DR. GRILLONE: No; there was not. It was not designed to look at
> quality of life.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: I just want to put the assessment of adverse events into the
> perspective. Of course, the trial wasn\'t designed to show any
> difference in terms of toxicity. Of course, not. For the original\--it
> is 4.2 versus 6.9. Those are not significant. The difference is
> something we should focus on. There is about a 3 percent difference.
> Of course, they are not going to be significant.
>
> Most of the time, they won\'t be significant because that would
> require a lot of patients to show a significant result. That would be
> after the drug is approved and in the postmarketing scenario. They
> will see more patients. Then you become significant.
>
> So I just want to put this assessment of the adverse event into
> perspective. The magnitude is what we should look at.
>
> DR. FONG: Why don\'t we take a look at the questions. Are there any
> objections to looking at the questions?
>
> **Questions and Vote**
>
> DR. FONG: What I would like to do is I would like to read the question
> and go around to each of you and have you comment on the answer, or
> answer the question.
>
> Kimberly just told me that we need to look at the questions that are
> attached to the agenda, not the book, the page following the agenda.
>
> The first question is\--maybe we will just start on one side of the
> room. I don\'t want to start with the statistician. Maybe we will
> start this way. Well, we will start with the statistician.
>
> The first question is has sufficient evidence been submitted to
> support the efficacy of Vitrase for the treatment of vitreous
> hemorrhage. Dr. Tan?
>
> DR. TAN: No; I don\'t think so. It is a yes or no question, so I will
> just say no.
>
> DR. FONG: Any comments to follow that?
>
> DR. TAN: First of all, the efficacy\--there is a conflict in the
> result in one trial\--there are two major pivotal trials. One is
> significant and the other one is not. Also, in terms of what is
> efficacy. Efficacy is not really well-defined.
>
> DR. FONG: Thank you, Dr. Tan.
>
> Dr. Phillips?
>
> DR. PHILLIPS: Bill Phillips. I would also say no. The three-month data
> lost the visual benefit, I believe, for the 55 International Units.
> Even just as far as the treatment outcomes, I would need to see that
> stratified more to really be sure that that was providing a treatment
> benefit over the watchful waiting of the saline group.
>
> DR. FONG: Dr. Chew?
>
> DR. CHEW: Emily Chew. Given the endpoints that were stated, I don\'t
> think we have that evidence for efficacy. One thing I would like to
> see, it is sort of on the next question, what additional studies are
> needed to establish, it would be nice if I were able to see the data
> that looked from\--
>
> DR. FONG: We will come to number two in a second. Let\'s just do
> number one.
>
> DR. CHEW: Okay.
>
> DR. FONG: Do you have any follow up to number one?
>
> DR. CHEW: No. I think it is the issue of the endpoint which we can\'t
> really have a good handle on in this particular study. I think, for
> me, vision would be a very important aspect of this given the
> composite was more difficult, although I know it is a different
> clinical question we are asking there.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. I would vote yes. The endpoints are not
> optimal. The study is not optimal. The data are not optimal, but there
> is a very, very clear trend in most of the subgroup analyses that
> there is a genuine change in the vitreous gel following the injection.
> Let me also comment, I don\'t disagree with Dr. Dunbar, but I think we
> can all learn from studies. We can all insist on better studies next
> time, but to state that we are lowering the bar by considering
> acceptance of this application seems to me to not necessarily be the
> question.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Jose Pulido. I would say it is minimally effective and
> there does appear to be a slight improvement in vision, improvement in
> peripheral visualization. I guess, with respect to what Dr. Dunbar
> said, I would hope that the next drug would have a better effect
> overall.
>
> DR. FONG: Is that an acceptable answer to FDA? No? We want a yes or a
> no.
>
> DR. PULIDO: Minimally, yes.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: Jeremiah Brown. I would say, in the application to improve
> visual acuity at two months that, yes, it was shown in both Vit-02 and
> 03 a statistically significant benefit. And then, in terms of
> resolution of vitreous-hemorrhage density, in both Vit-02 and Vit-03,
> showing a statistically significant benefit at two months. So, in that
> limited application, that is the benefit that I see. That is the
> efficacy.
>
> DR. FONG: What is your answer?
>
> DR. BROWN: Yes.
>
> DR. FONG: Dr. Gates?
>
> DR. GATES: I am certainly torn between both camps here. I believe that
> efficacy in the population as a whole, and scientifically, wearing my
> scientific hat, I would say no. Taking care of the individual, I think
> there are individual patients out there that would certainly benefit.
> But I think I have to vote, as far as for the population as a whole,
> and say no. The data doesn\'t show.
>
> DR. FONG: Donald Fong. I wanted to commend the sponsor on tackling a
> tremendously difficult problem, being the first in the field to
> investigate the treatment for vitreous hemorrhage, tremendously
> difficult endpoints that are hard to come by. I think it is a very
> important area to study.
>
> However, I am concerned about the surrogate endpoint. What I am
> concerned about is the connection between the endpoint and what we are
> ultimately interested in which is vision. I don\'t see that connection
> being presented and being supported. So I have concerns about the
> endpoint and I also have concerns about replicability.
>
> It seems like each study shows positive findings in different
> endpoints. So that suggests to me that chance might be playing a role
> here. So I would answer no.
>
> Dr. Feman?
>
> DR. FEMAN: I vote no, also. I believe that the problem is that the
> endpoints that we are looking at are not endpoints that were accepted
> by the FDA as was initially proposed. Therefore, if we are looking at
> just the evidence that was submitted in terms of what we are expecting
> to see, the answer is no.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: I also vote no. I share Dr. Brown\'s observations that, at
> two months, visual acuity and density of hemorrhage did show
> statistical significance and it was replicated between both trials.
> But, again, as others have observed, there were so many endpoints.
> These were not the primary endpoints as the study was initially
> designed.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: I guess the way the question is worded, I would vote no,
> too, given my concerns about the surrogate endpoint, like Dr. Fong\'s.
> The marginal benefit of three-line vision and hemorrhage at two and
> then not being carried through to three months, and then it not being
> shown with the primary endpoint.
>
> MS. KNUDSON: Paula Knudson. I am persuaded to say yes on the basis
> that if it does provide some patients with earlier and better
> management, I think it is worth having.
>
> DR. FONG: I would like to move on to Question No. 2, if there are no
> objections. Kimberly wanted me to report the vote, which I have, which
> is four for yes and eight for no to Question No. 1.
>
> Question No. 2 is, \"If not, then what additional studies are needed
> to establish the efficacy of this product?\" To answer this very basic
> question, I am going to start with Paula.
>
> MS. KNUDSON: I am insufficiently well versed to know what kind of
> studies should be designed.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: In addition to a lot of things I would like to know
> including how it might just stack up to vitrectomy surgery. I think
> the one thing that I would like to know more about is just plain
> quality of life. In reading this, as was clarified, the pain might not
> be what it seems when you are reading this. A lot of these things
> might shake out a little bit differently if you were really asking
> patients detailed questions about what their experiment was and the
> value of it.
>
> DR. FONG: Is that enough clarification for you? Okay.
>
> Dr. Dunbar?
>
> DR. DUNBAR: I would be interested to know if there is some subgroup of
> these patients, if all the of the diabetics were sorted out, if
> patients with earlier hemorrhages were sorted out in these kinds of
> situations, if there is a subgroup this is especially useful for,
> perhaps even just redesigning the study based on the information here,
> the density reduction at two months and the visual acuity improvement
> at two months, may be enough to help the company to achieve approval.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: I am sort of surprised that the company did not pursue the
> surrogate endpoints to an acceptable level for FDA approval. Somewhere
> in the packet that we received, they had initially suggested some
> surrogate endpoints and then it was not completed. I think that is
> what needed to be done is to prove that the surrogate endpoints that
> seem to have some value to them are still worthwhile. I think they
> need to look at these surrogate endpoints and make them an acceptable
> endpoint.
>
> DR. FONG: Donald Fong. I go back to what I have said earlier. When I
> do anything to patients, I want to know that I am doing something that
> is helpful to them. What I like to see is evidence to support that
> this actually is doing something.
>
> I think I would like to see that they are getting some useful vision
> back or that it is preventing a vitrectomy and, if they are getting
> vision back, that it is persistent. So I would like to see sort of an
> analysis of useful vision, vitrectomy rates and maybe the time
> involved, a Kaplan-Meier analysis.
>
> I agree with what Dr. Steidl said and that is that too often\--I often
> do this myself\--forget the patient\'s perspective. I would really
> like to see how the patient feels about this, whether their quality of
> life improves, where they are able to recognize people better, they
> are more able to ambulate better, something along those lines to
> support its use.
>
> Dr. Gates?
>
> DR. GATES: I would also concur and like to see some data with quality
> of life.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: Jeremiah Brown. I would also like to see quality-of-life
> data and also validation of the surrogate endpoints. I think that
> these are very useful. If we could show that earlier treatment,
> earlier visualization actually made a difference in the outcome for
> the patient, then that would make me feel even more positive about it.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: I had voted yes, so, because of that, I will forego
> answering Question No. 2.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. I would like to defer my response to
> Question 3 except to point out that I think these endpoints were
> poorly stated. To look at this drug as a drug to improve vision, or to
> improve quality of life just because it is stuck in there, is not
> particularly relevant. I don\'t think that, theoretically, you really
> would expect that without some kind of additional therapy in most
> cases.
>
> DR. FONG: Dr. Chew
>
> DR. CHEW: I don\'t have much more to add, other than the quality of
> life. I think it is very important from the patient\'s point of view.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: I had coming at the end of the line. I have to echo
> everything everyone said about the quality of life, since Vitrase is
> not really designed to treat the underlying condition but just treat
> the vitreous hemorrhage. So we need to know how much is that treatment
> improving their quality of life versus a gold standard for treating
> vitreous hemorrhage such as a vitrectomy.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: I would like the company to revisit what are the really
> expected benefits for this product. If the product is really based on
> the mechanism or the size, the product really leads physicians to
> better diagnosis, then build the endpoint on that.
>
> DR. FONG: Any more observations about Question 2? Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. Don, I would like to make one additional
> comment regarding quality of life. It is critical. We all believe in
> it, but Paul Lee, of Duke, has done extensive analyses and interviews
> with patients. There are certainly many patients that have been
> optimally treated with heavy scatter photocoagulation who have had
> blindness prevented\--no doubt about it\--who are exceptionally
> unhappy. So I would recommend that they are very careful on how they
> structure these quality-of-life interviews because not every patient
> appreciates all you have done for them as opposed to to them,
> Don\--that you have done for them.
>
> DR. FONG: As a retina specialist, I echo that. Let\'s move on to
> Question No. 3. \"Are additional analyses of the current data needed
> to understand the efficacy or safety of Vitrase for the treatment of
> vitreous hemorrhage?\"
>
> Dr. Tan, would you mind if I started with you, again?
>
> DR. TAN: Okay. If they can get some\--I don\'t know if those data are
> available. It seems, for the final outcome, whether they would need a
> better outcome from the patients with vitrectomy due to maybe an
> earlier diagnosis of the possible clearing of the blood. So this type
> analysis, a time-to-event analysis, would be useful.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: I guess one thing we were looking for, or looking at,
> would be if there was maybe a little bit better visual-acuity
> qualification early on, sort of admitting we can\'t do a logMAR for
> the 28,000, as he indicates, maximum number of patients. I would like
> to see that, but I think that would be very difficult.
>
> DR. FONG: Actually, I was reminded that Question No. 3 is a yes/no
> answer. So I have to go back to Dr. Tan and ask him, are additional
> analyses of the current data needed to understand the efficacy or
> safety of Vitrase for the treatment of vitreous hemorrhage? Yes or no?
>
> DR. TAN: That would be yes.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: I will vote yes.
>
> DR. FONG: Dr. Chew?
>
> DR. CHEW: I would say yes. I would like to go down the same line that
> Bill Phillips is going down. I would like to see analyses looking at
> that very severe n and, instead of giving them one line for each jump
> is to consider them all to be at zero and see what happens, what
> proportion would actually gain fifteen letters if we start off with
> that. I can\'t tell from the data here, although, at one month and two
> months and three months, and see whether there is some improvement
> from that.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. I initially responded yes, so I am
> responding yes again, as illogical as that may sound. I kind of agree
> with what Dr. Dunbar brought up and that is, if you can, perhaps,
> restratify these cases and particularly look at the relatively fresh
> hemorrhages and somehow identify what the doctor was able to do for
> that patient, or to not do, and comparing the control and the
> treatment arms.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Jose Pulido. Yes, there are other data that would be
> worthwhile looking at. The Bull-Dunbar effect, stratifying in terms of
> how long the hemorrhage has been there, determining whether there are
> differences and number of patients on Coumadin in one group versus
> Coumadin in the other group. Mentioned time and again, are differences
> in race and it might be worthwhile, if there are any second eyes that
> have been treated, to see if there is any inflammatogenic effect in
> the second eyes.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: I would also say yes. The visual-acuity issue is probably
> the most important one from what I saw. I was looking at some data
> that I had during the break. Jerry Fishman, who does a lot of work on
> patients with low vision due to hereditary retinal diseases, has a
> scale that he has used for assessing LOGmar in patients who cannot
> read 20/400, even down to count fingers.
>
> I just noticed that the numbers that he chooses are not as
> beneficial\--well, they are quite a bit lower than what was used for
> this study. So 1.84, I think it was, count fingers, he uses a much
> lower number at 2, or a greater number; poorer vision, in other words.
>
> So, looking at the assessment of the LOGmar and if that were changed
> how that would affect the results. That is another thing that I would
> like to look at. Then the third was the stratifying based on the time
> of the vitreous hemorrhage.
>
> DR. FONG: Dr. Gates?
>
> DR. GATES: I would also like to see that stratification and I would
> say yes.
>
> DR. FONG: I would answer yes, also. What I really want to do is really
> understand what is happening. I agree with Jose and Jeremiah and Pat,
> what they said, that something is happening here. I really want to
> figure out what is happening, these patients that we are getting some
> transient clearing. What is being done? Does that actually lead to a
> treatment that affects the final visual acuity.
>
> So I need more sort of connection between final visual acuity and the
> proposed outcome. Also, I agree with Dr. Dunbar that it would be
> helpful to know whether this treatment might be effective in certain
> groups.
>
> Dr. Feman?
>
> DR. FEMAN: I agree with you all. I agree, yes, that additional
> analyses of the current data are needed to understand the efficacy of
> Vitrase. A lot of the data is currently available, it seems, and we
> just have not looked at it. But I think we also need more data, but to
> answer the specific question, yes.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: A minor point, in addition to the stratification, that I
> touched upon earlier. I would be interested to see a subgroup analysis
> of patients with previously diagnosed glaucoma for safety issues.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: I guess yes, in answer to the question, simply because I
> think further analysis might convince someone such as myself to change
> their opinion about the efficacy. But I agree about the early versus
> late treatment. That would be very interesting and of value in terms
> of functional vision.
>
> Another thing I am sort of curious about is maybe a little bit more
> detail than just three steps, who had it, who didn\'t, for those who
> had improvement, what percentage in the treated group had five steps,
> six steps, seven steps, versus the control. It might be interesting to
> know that, if you did get an effect, the effect in the treated group
> would be bigger. It would be curious.
>
> DR. FONG: Paula?
>
> MS. KNUDSON: Yes. I would like to see the data mined for who are these
> patients who actually had the benefit. Is there a difference in age?
> Is there a difference in race? I would just like to know more about
> those people and see whether we could do something along those lines,
> maybe structure the drug specifically for a type of patient, specific
> type of patient.
>
> DR. FONG: There is unanimity that there needs to be additional
> analysis. That is the answer to Question No. 3. Let\'s go ahead and
> move on to Question No. 4, if there are no objections. \"Should the
> potential interaction, positive or negative, of Vitrase with current
> treatments for Vitrase hemorrhage be evaluated?\"
>
> I know it is unfair, but Ms. Knudson?
>
> MS. KNUDSON: Of course, I would have to say yes. I think it would be
> extremely important to know.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: I agree yes, but it is hard for me to formulate a response
> at this time. If it were possible to just take equal groups and
> compare them to vitrectomy, it would be interesting for me. But I am
> not sure that that is appropriate. I am not sure what the right study
> is, but I think it would be\--if it could be properly thought out, the
> answer is yes.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: Actually, no. I think that the company described in
> various different ways the relationship between vitrectomy and the
> drug.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: I would vote yes. I think that the drug might be very
> effective in preplanning doing a vitrectomy. In other words, if what
> we are seeing is the correct interpretation, and I am not sure if that
> is, this would clear up the eye in such a manner that one could,
> perhaps, plan a vitrectomy although one does that when you are doing a
> vitrectomy. So I don\'t know how the drug would offer any benefit. But
> I still would vote yes from that perspective.
>
> DR. FONG: I will answer yes. I think that the interaction between
> vitrectomy and use of this product needs to be investigated further.
> This is sort of what I said earlier, that it is hard for me to tell
> what Vitrase is doing if we are going to do a vitrectomy very soon
> after diagnosis anyway.
>
> Dr. Gates?
>
> DR. GATES: I would also say yes.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: Jeremiah Brown. Yes.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: I would say yes, only for negative, would it\--just
> looking at the present data and not having to do another study for the
> company, does the use of Vitrase in any way cause a deleterious effect
> following vitrectomy to vision? I don\'t think any further study has
> to be done just looking at the present data.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. I would agree with what Dr. Pulido just
> said. There really is no other treatment for this and the only
> question might be how it alters the performance of a vitrectomy. A
> vitrectomy is simply designed to create a liquid-filled cavity also
> eliminating the cortical vitreous. This drug does the first half of
> that. Since there is no other treatment but vitrectomy, what Jose said
> is something I agree with.
>
> DR. FONG: Dr. Chew
>
> DR. CHEW: I would agree with that also.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: I would also say no. They essentially already have that
> data in that if the Vitrase works and your view is clear enough to
> either see, nothing needs to be done, they need or laser or a
> combination of laser and vitrectomy. You are already going on to those
> endpoints so I don\'t think anything additional needs to be done for
> that. So the answer is no.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: My answer is that I agree exactly with Dr. Pulido, they
> don\'t need a concurrent comparative study because they don\'t really
> know the endpoint should be there. I think, in addition, what would be
> interesting or useful for us is some type of maybe a historical
> comparison versus a concurrent study.
>
> DR. FONG: That is a yes or a no?
>
> DR. TAN: Technically, a yes.
>
> DR. FONG: Let me go back to Dr. Phillips. I think we didn\'t write it
> down. Was yours a yes or a no?
>
> DR. PHILLIPS: No.
>
> DR. BROWN: May I amplify just to give a reason? The one thing that I
> noticed in the data was that trend toward fewer vitrectomies in the
> Vitrase group. It would be very interesting to know what were the
> indications for those vitrectomies. If this is going to be a real
> thing, that perhaps we reduce the need for vitrectomy by 5 percent,
> why is that and just to see what were the indications.
>
> DR. FONG: So the tally for the answer to Question 4 is two no, ten
> yes. So, if there are no objections, I would like to proceed to
> Question No. 5.
>
> DR. CHAMBERS: Dr. Fong?
>
> DR. FONG: Yes? Dr. Chambers?
>
> DR. CHAMBERS: I would come back a little bit to the question we just
> asked and ask whether there is a feeling within the committee that
> something like the following scenario, which I want to propose, would
> be useful looking at. It has been discussed that there is a
> possibility that Vitrase would more liquify the vitreous making
> vitrectomy easier, faster\--easier in some fashion, which was not
> collected in the present study although, obviously, vitrectomies were
> done.
>
> Is there a feeling, if you were to go back and look at vitrectomy
> time, surgical time, would that be reflective of an easier surgical
> case?
>
> DR. FONG: Do you want a discussion or do you want a vote?
>
> DR. CHAMBERS: I want to know whether there is a general feeling that
> that would be a useful parameter to look at.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: I don\'t think so because the underlying pathology that
> caused the hemorrhages is as important or more important than the
> amount of time it takes to get that hemorrhage out of there. So there
> would be so much data that would have to be looked at retrospectively
> that it would be very difficult to do. Again, my concern more is is
> there a negative effect, not if there is a positive effect.
>
> DR. WILKINSON: Pat Wilkinson. I would agree with the answer no for
> this trial. I would think, based on what the sponsor\'s consultants
> said, we would expect removal of blood to be somewhat faster but the
> guts of a vitrectomy operation in a diabetic patient are the interface
> between the cortical vitreous and the retina.
>
> It is extensive. You have got a very, very difficult case. If it is
> simply an insertion on the optic nerve, it is very, very simple. So
> the essence of the operation and the difficulty of the operation and
> the length of the operation are going to be much more related to the
> underlying vitreoretinal pathology than to simply removing the blood.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: I will take the other tack, although Pat is a friend of
> mine. I disagree with the concept in that I think that there may be
> something special to offer patients with this in that, if you can
> reduce the time in the operating room as a hypothetical case, imagine
> a patient with heart failure and renal failure that you want to just
> operate on as little as possible because of their danger to them of
> the anesthesia, whether local or any other type of anesthesia.
>
> This would, perhaps, shorten your operating time by a significant
> amount. Would that be a benefit that this agent would offer?
>
> DR. WILKINSON: Pat Wilkinson, again. I agree. There is no doubt that
> it would shorten the operating-room time, but you are talking about,
> perhaps, one minute versus seven minutes. When the dissection and
> delamination at the vitreoretinal interface can take an incredibly
> much larger amount of time.
>
> So the variable of time for this surgery in this indication, I think,
> would be a difficult study to set up and should probably be limited to
> very specific indications for the vitrectomy.
>
> DR. FONG: Thank you. Let\'s move on to Question 5. \"Are there adverse
> experiences that are of particular concern for this product?\" We will
> start with Ms. Knudson.
>
> MS. KNUDSON: Paula Knudson. I was struck by the amount of pain that
> people reported. I am unclear and would like more clarification. Does
> every kind of injection into the eye produce this kind and amount of
> pain, because I don\'t know that.
>
> DR. FONG: That is an interesting question. I guess before we answer
> that, let\'s have a discussion about that issue. Maybe Wiley and
> Jennifer can give us maybe some baseline on what you guys think of it.
> How does it compare, let\'s say, to Vitravene or gancyclovir
> injections?
>
> DR. CHAMBERS: Wiley Chambers. Actually, I don\'t think I am probably
> the best one to be answering it in this particular case since I am
> reading the papers from the sponsor. You have people who have actually
> been in the room with the patients that have received it. I would
> suggest they are better ones to ask.
>
> DR. FONG: Maybe, Barry, you gave us some data before. Maybe you can
> sort of tell us again and compare that against gancyclovir injections
> and so forth.
>
> DR. KUPPERMAN: I may, in fact, have the most experience here with
> giving injections because of my history of treating AIDS patients with
> gancyclovir. I saw and I did have a fair number of patients that we
> have treated with the Vitrase. I saw difference between the responses
> to the two types of injections. That includes also having done a
> significant number of triamcinolone injections and other sorts of
> injections as well for endophthalmitis, et cetera. Endophthalmitis, of
> course, is typically more associated with pain because of the more
> inflamed eye, but this is very similar to the sort of site-injection
> pain associated with either a gancyclovir, foscarnate injection for an
> AIDS patient or with a triamcinolone injection for a patient with
> diabetic macular edema.
>
> DR. FONG: Barry, do you remember, sort of, the number or the
> percentage of pain that was reported for those studies? Do you happen
> to remember that?
>
> DR. KUPPERMAN: No. Again, this is simply a matter of asking\--the
> patient\'s complaint and the comment about the pain and the irritation
> that followed. It was typically similar across all these types of
> injections. We do injections on a regular basis, and there was nothing
> that separated the subset of patients that received Vitrase injections
> from the patients who received all the other types of injections I
> have been involved with.
>
> MS. KNUDSON: I was just curious whether it was the injection, itself,
> or whether it was the drug, itself, that was inducing the pain.
>
> DR. KUPPERMAN: There was no evidence that it was the drug, itself. It
> was the site injection from the needle stick.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: My answer is no.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: My answer is yes, I am concerned about the iritis.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: My answer is no.
>
> DR. FONG: I am the sort of a person who likes more information. So, do
> I have particular concern? My answer would be yes, just until I had
> more information to understand exactly what is going on with those
> retinal detachments. Is it related to the injection or not, just sort
> of more analysis along those lines.
>
> Also, I am concerned about the issue of pigment and inflammation that
> Dr. Pulido raised especially if one is concerned about, or one is
> interested in, injecting in both eyes. Certainly, we would not want to
> insight a severe inflammation response with injection into the second
> eye.
>
> Dr. Gates?
>
> DR. GATES: I am interested in the mechanism of action of the hypopyons
> although I feel like the company has a good handle on what is going on
> and how to handle and how to follow these folks. I think that is
> something you are going to see.
>
> DR. FONG: No concern? Okay.
>
> Dr. Brown?
>
> DR. BROWN: Jeremiah Brown. My answer is yes. My basic issue is the
> saline rate of retinal detachment, 5.8 percent, 55 International units
> of Vitrase rate was 10.3 percent. If, in fact, it is that the view is
> clearing, another thing that could be done is to go back and look at
> those records and look at the patients who never had\--who did not
> have a detachment early but maybe still had vitreous hemorrhage so we
> couldn\'t see that.
>
> How about when that hemorrhage eventually cleared? Do those rates
> start coming up to match each other? That would be one way to look at
> it.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Yes, for the concerns already raised.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Pat Wilkinson. A mild yes for the issues that you and
> Jose brought up.
>
> DR. FONG: Dr. Chew
>
> DR. CHEW: Yes, just for the retinal detachments in particular.
>
> DR. CHEW: Dr. Phillips?
>
> DR. PHILLIPS: No.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: Yes. I feel that the rate for retinal detachment is too high
> for me.
>
> DR. FONG: So the tally for Question No. 5 is eight yes and four no.
>
> With no objections, I would like to proceed to Question 6. \"Is there
> a concern about the death rate observed in these studies?\" Dr. Tan?
>
> DR. TAN: No. It seems the death rates are comparable to the patient
> population.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: No, for the same reason.
>
> DR. FONG: Dr. Chew
>
> DR. CHEW: No. We know that patients with proliferative disease have a
> high rate of mortality. I just hope that the next studies that they
> take this into account for their power-size calculation because it is
> significant.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: No.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: No.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: No.
>
> DR. FONG: Dr. Gates?
>
> DR. GATES: No.
>
> DR. FONG: Donald Fong. No.
>
> Dr. Feman?
>
> DR. FEMAN: No.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: No.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: No.
>
> DR. FONG: Ms. Knudson?
>
> MS. KNUDSON: No.
>
> DR. FONG: So it is unanimous no to Question No. 6. I would like to go
> to Question No. 7. \"Do the benefits of using Vitrase outweigh the
> risks in the treatment of vitreous hemorrhage?\" I forgot which side I
> started on. Paula?
>
> MS. KNUDSON: Paula Knudson. I think yes, not the most positive yes,
> but yes.
>
> DR. FONG: Dr. Steidl?
>
> DR. STEIDL: In view of everything said so far, this is a difficult
> question to answer. I think I might give a mild yes. We acknowledge
> the difficulty with statistical significance but both the benefits and
> the risks are small, so I guess yes, with a few qualifications.
>
> DR. PULIDO: Can I ask a point of clarification? The first question
> was, has sufficient evidence been submitted to support the efficacy.
> So if people have voted no for efficacy, can they vote yes for
> benefits?
>
> DR. FONG: I think, to be consistent, I will defer to Wiley and
> Jennifer and see what their experience was. It seems like, if you are
> going to say that there is no evidence submitted, insufficient
> evidence. It is hard to be consistent and say that there now is a
> benefit. Scott? Dr. Chambers?
>
> DR. CHAMBERS: We bring products before the committee because we have
> not made final decisions. We write questions because we don\'t know
> what the vote is going to be ahead of time. So we try and provide the
> different contingencies. The assumption was that this question is more
> relevant if the first question comes out a majority of people thinking
> there is sufficient efficacy and then there is a question of efficacy
> versus risk.
>
> If there is not felt to be sufficient efficacy initially, then we
> think it was unlikely that you would come up with a vote that said
> that the benefits outweigh the risks in the last question, but we were
> trying to cover the various potential contingencies not knowing how a
> vote would come out ahead of time.
>
> DR. FONG: Would you like us to poll the yes\--no? I hear a no from Dr.
> Bull.
>
> DR. BULL: Jonca Bull. I guess the committee will have to weigh whether
> or not there may be some internal contradiction as Wiley has
> articulated relative to the questions trying to anticipate the
> contingencies, as he stated. If there is a consensus that the vote on
> the first question, on efficacy, it sort of puts you in somewhat of a
> dilemma here to comment on benefits and risk when the comments we
> received before don\'t go in the direction of having established
> sufficient efficacy. So I will defer to you all as to whether or not
> you want to pursue responding or to just overall provide some
> comments.
>
> We are hearing rather tepid responses from the folks who have
> responded already.
>
> DR. FONG: Wiley, would you accept just an overall discussion instead
> of a yes/no answer to this?
>
> DR. CHAMBERS: Yes.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Since I brought this question up, I would like, then\--if
> people are saying yes for this last one, I would like them to
> reconsider, then, their vote for the first one.
>
> DR. STEIDL: Let me say something to that. Maybe with more
> clarification of what we are answering, it would be easier. I take the
> first question to be something quite specific relative to statistical
> proof and the last one a letter of the law versus spirit of the law.
> Is there a time when you would use it where you are thinking maybe you
> don\'t have an alternative, is this a dangerous drug.
>
> I am still not completely clear what the question is asking but, if it
> is a broader question, I could say very mildly yes, but depending upon
> how we are approaching it.
>
> DR. FONG: I think there are two issues. Wiley said you don\'t need to
> vote yes or no and second is that, if you have specific comments, I
> think you definitely want to report it so that the company and the FDA
> knows what the issues are.
>
> DR. CHAMBERS: This is Wiley Chambers. The assumption was that this
> question would only come up if we decided or if the committee had
> decided there were sufficient benefits and sufficient efficacy
> established in what was Question 1. We then asked other questions to
> get a fuller discussion to try and get additional aspects as far as
> the analysis.
>
> Remember, the agency will take back all this information and make a
> determination whether we think the drug should be on the market or
> not. That is not the question that we are asking, per se. What we are
> asking for are are there clear benefits that outweigh the risks for
> the particular drug in this particular case based on the information
> you have seen.
>
> We understand and will take in all the various comments and we
> understand the issues of the individual patients and the other factors
> that go in with providing treatment. But we are looking at the overall
> benefits versus the risks based on the data that you have seen
> presented.
>
> DR. STEIDL: I will say no. I think it is an issue\--
>
> DR. FONG: You don\'t need to say yes or no, just so you know.
>
> DR. STEIDL: All right. I think what this brings up are some
> interesting issues. First of all, the person who might not be able to
> have a vitrectomy and a number of other scenarios where, if you had
> something available where someone was scared of surgery, would you
> consider using it if you didn\'t think that the risks were too high.
>
> Again, maybe just as an adjunct to the greater question if you are
> trying to look to other areas for insights, I think that maybe at face
> value, this should be linked to Question 1. But I am taking it as a
> broader question. I think there might be situations where you want to
> consider using it I guess is all I can say, if it were available.
>
> DR. FONG: So, to summarize, I think you would say yes you could
> imagine a situation if it can be shown to be effective.
>
> DR. STEIDL: Right.
>
> DR. FONG: Dr. Dunbar?
>
> DR. DUNBAR: I appreciate Dr. Steidl for clarifying this because the
> way he expressed it is the way that I feel. This also gets back to the
> stratification issue. I am very hopeful that we will be able to
> determine a subgroup of patients that this is helpful for, but in
> light that I voted no for the efficacy, I would have to vote no the
> way things stand at this point in time.
>
> DR. FONG: Dr. Feman?
>
> DR. FEMAN: To read the question the way it is phrased, the risks in
> the treatment of vitreous hemorrhage using this is not really much
> different than the risk of injecting saline except for the hypopyon
> and the other things that we find are easy to treat.
>
> The benefits potentially could outweigh the risk of injecting saline
> but just barely. So I think, to answer this question the exact way it
> is phrased, I would say yes even though I voted no on the first
> portion.
>
> DR. FONG: I agree with what has been said so far which is that the
> risks are relatively low. However, I am not convinced of the benefit
> so, if you have a no on the numerator, let\'s say, or one portion of
> the equation, then the whole equation would have to be no.
>
> Dr. Gates?
>
> DR. GATES: I would concur. I am also optimistic that there is a
> subgroup of patients, perhaps a very, very sick group of patients or a
> fearful group of patients that can benefit from this in the data that
> I have seen so far.
>
> DR. FONG: Dr. Brown?
>
> DR. BROWN: Yes.
>
> DR. FONG: Dr. Pulido?
>
> DR. PULIDO: Yes, minimally.
>
> DR. FONG: Dr. Wilkinson?
>
> DR. WILKINSON: Yes.
>
> DR. FONG: Dr. Chew
>
> DR. CHEW: I would also say yes. I think that my answer is similar, I
> think, to what Scott was saying earlier that statistically looking at
> it in general, it was difficult to give an efficacy. But I can imagine
> some clinical situation where I think it would be very useful and
> there are some patients who may benefit from this.
>
> I am not that a separate analysis can be done in this case. It is such
> small numbers to begin with that it is always dangerous to go on
> subgroups, but I am sure there are probably some patients who really
> are benefitting from this.
>
> DR. FONG: Dr. Phillips?
>
> DR. PHILLIPS: To be consistent with how I voted on No. 1, I am going
> to say no. But I do think that a specific subgroup, either medically
> unable to go through a vitrectomy or just literally refuse to go
> through surgery may benefit. But, looking at the overall group of
> patients with vitreous hemorrhage, I will say no.
>
> DR. FONG: Dr. Tan?
>
> DR. TAN: I understand we don\'t have to vote here, but my answer is
> no, not as presented.
>
> DR. FONG: We have a split vote, six for yes and six for no. Is there
> anything else that the FDA or the sponsor would like\--
>
> DR. CHAMBERS: Nothing from the FDA\'s perspective except to thank you
> very much for your time and efforts.
>
> DR. KUPPERMAN: I don\'t mean to interrupt, but I got seven/five. I\'m
> sorry. I guess I would like to sort of clarify as I was running
> through my math. I didn\'t get whether Scott ended up being a yes or a
> no because that would have made it six/six versus seven/five. I don\'t
> know if that matters or not, but when I was doing the tally, I had
> seven/five. That is the only reason I want to clarify.
>
> MS. TOPPER: According to the records, Scott did change his mind to no;
> is that correct?
>
> DR. FONG: Scott, what was your vote?
>
> DR. STEIDL: I am a little confused about the question, personally. But
> I did say similarly\--my feeling is similar to what Stephen Feman
> stated that, although I said no to the first, I am thinking about the
> last question in a broader sense. So I guess you could put me as a
> yes. I could clarify that in detail, if you want, but\--I think that
> there probably are subsets and patients where I would consider it so I
> kind of feel that I would have to say yes to this even though it may
> seen contradictory.
>
> DR. FONG: Scott, when was the last time you stopped beating your wife?
> This concludes the subcommittee meeting of the Ophthalmic Drug
> Advisory Committee of the FDA. The final vote was seven yes, five no
> looking at Vitrase sponsored by ISTA Pharmaceuticals. Thank you.
>
> \[Whereupon, at 2:45 p.m., the meeting was adjourned.\]
>
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