SGDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> DERMATOLOGIC AND OPHTHALMIC DRUGS
>
> ADVISORY COMMITTEE
>
> Thursday, September 25, 2003
>
> 8:00 a.m.
>
> Holiday Inn
>
> Bethesda, Maryland
>
> P A R T I C I P A N T S
>
> William Gene Gates, M.D., Acting Chairman
>
> Kimberly Littleton Topper, M.S., Executive Secretary
>
> VOTING SPECIAL GOVERNMENT EMPLOYEES:
>
> Mark A. Bullimore, MCOptom, Ph.D., FAAO
>
> Center for Devices and Radiological Health Ophthalmic
>
> Devices Panel Member
>
> Emily Chew, M.D.
>
> Stephen S. Feman, M.D.
>
> Lewis C. Gordonson, M.D.
>
> Richard Gorman, M.D., Pediatric Committee of the
>
> Anti-Infective Drugs Advisory Committee
>
> Marijean M. Miller, M.D.
>
> Scott M. Steidl, M.D.
>
> Constance E. West, M.D.
>
> GUEST:
>
> R. Todd Plott, M.D.
>
> FDA STAFF:
>
> William Boyd, M.D., Clinical Team Leader,
>
> Division of Anti-Inflammatory, Analgesic and
>
> Ophthalmic Drug Products
>
> Jonca Bull, M.D., Director Office of Drug Evaluation V
>
> Wiley A. Chambers, M.D., Deputy Director, Division of
> Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Introductions,
>
> William Gene Gates, M.D. 4
>
> Conflict of Interest Statement,
>
> Kimberly Littleton Topper, M.S.,
>
> Executive Secretary 6
>
> Introduction and FDA Presentation,
>
> Wiley Chambers, M.D. 8
>
> Novartis Presentation:
>
> Introduction, Ken Green, Ph.D. 19
>
> Definition, Prevalence, Natural History and
>
> Risk Factors of Myopia in the U.S.,
>
> Jane Gwiazda, Ph.D.,
>
> New England College of Optometry 21
>
> Consequences of Myopia,
>
> Joseph Miller, M.D., MPH,
>
> University of Arizona 27
>
> Proposed Clinical Study Design,
>
> Karla Zadnik, O.D., Ph.D. 52
>
> Overall Summary, Ken Green, Ph.D. 65
>
> Committee Discussion 67
>
> Committee Discussion of Questions from the FDA 136
>
> [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 Introductions**
>
> DR. GATES: Good morning. I would like to welcome you to the meeting of
> the Dermatologic and Ophthalmic Drug Advisory Committee. I am William
> Gates, Nashville, Tennessee, and I will be the acting chair today.
>
> First, I would like to start off with having each of us introduce
> ourselves, and we will begin from my left and go to the right. So, I
> will have you start, Dr. West.
>
> MS. LITTLETON TOPPER: When everyone speaks, please make sure you press
> the button; release it; the red light will come on; speak into the
> microphone and then turn it off when you are finished. Thank you.
>
> DR. WEST: I am Constance West. I am Director of Pediatric
> Ophthalmology at Cincinnati Children\'s Hospital in Cincinnati, Ohio.
>
> DR. GORDONSON: I am Lewis Gordonson. I am originally an optometrist
> from Iowa State and am now Professor of Ophthalmology at New York
> University in New York.
>
> DR. BULLIMORE: My name is Mark Bullimore. I don\'t normally speak like
> this; I have a cold. I am Associate Professor of Optometry and Vision
> Science, from Ohio State University.
>
> DR. CHEW: I am Emily Chew. I am from the National Eye Institute. I am
> an ophthalmologist and epidemiologist.
>
> DR. FEMAN: I am Stephen Feman. I am an ophthalmologist. I am a
> professor of ophthalmology at St. Louis University.
>
> DR. MILLER: I am Marijean Miller. I am a faculty member at Children\'s
> National Medical Center here, in Washington, D.C.
>
> DR. STEIDL: I am Scott Steidl. I am a retina specialist at the
> University of Maryland, in Baltimore.
>
> DR. BOYD: I am William Boyd. I am an ophthalmologist, clinical team
> leader with the FDA in the Division of Anti-Inflammatory, Analgesic
> and Ophthalmologic Drug Products.
>
> DR. CHAMBERS: I am Wiley Chambers. I am the Deputy Director for the
> Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug
> Products.
>
> DR. GATES: Thank you. Next I will have Kimberly begin by reading the
> conflict of interest statement.
>
> **Conflict of Interest Statement**
>
> MS. LITTLETON TOPPER: The following announcement addresses the issue
> of conflict of interest with respect to this meeting and is made a
> part of the record to preclude even the appearance of such at this
> meeting.
>
> The topics of today\'s meeting are issues of broad applicability.
> Unlike other issues before the committee in which a particular product
> is discussed, issues of broader applicability involve many industrial
> sponsors and academic institutions. All special government employees
> and federal guests have been screened for their financial interests as
> they may apply to the general topics at hand. Because they have
> reported interests in pharmaceutical companies, the Food and Drug
> Administration has granted general matters waivers to the following
> SGEs which permits them to participate in today\'s discussions: Dr.
> William Gates, Dr. Richard Gorman, Dr. Stephen Feman and Dr. Mark
> Bullimore.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> Because general topics impact so many institutions, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> member, consultant and guest.
>
> Dr. Todd R. Plott, who will be down in just a moment, has been invited
> to participate as a non-voting industry representative acting on
> behalf of regulated industry.
>
> FDA acknowledges that there may be potential conflicts of interest
> but, because of the general nature of the discussion before the
> committee these potential conflicts are mitigated.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participant\'s 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 firm whose product they may wish to comment upon.
> Thank you.
>
> I would also like to state that some of you might notice we have one
> committee member from the full Dermatologic and Ophthalmic Advisory
> Committee and we are required to have two. Our second one, at the last
> minute, had a problem and was unable to come and we made the
> determination that the meeting was more important than canceling it
> because of the inability to have two members. Thank you.
>
> DR. GATES: Thank you, Kimberly. Next I will call on Dr. Chambers for
> the FDA presentation.
>
> **Introduction and FDA Presentation**
>
> DR. CHAMBERS: Thank you, Dr. Gates and good morning, everyone.
>
> The purpose of today\'s meeting is to try and discuss, on a
> preliminary basis, the information that the FDA needs to try and
> develop guidance documents for the development of drug products or
> therapies to prevent the slow progression of myopia. The FDA has a
> number of different guidance documents in different levels of
> development. One of the first processes is to try and collect
> information. The purpose of this meeting is to try and do just that as
> a first step.
>
> We recognize that myopia is a very common disease, if you want to call
> it disease; condition if that is what you want to call it. There are
> lots of different terms that are used for it but the prevalence
> estimate for myopia is somewhere on the order of 20-50 percent in the
> United States so it affects a lot of people.
>
> The potential use of any product, we believe, that would try and slow
> or prevent myopia is likely to occur in children whose parents are
> myopic, or where there are parents that believe their children will
> become myopic because we believe that the most likely case for any
> drug products will be in the early stages, basically developing
> pediatric development. Unlike the other treatments for myopia, such as
> glasses, such as contact lenses, such as different refractive
> procedures, we think drug products are much more likely to be used
> early on as opposed to later in life. But that does not preclude that
> there may be products developed later on and, to the extent that that
> comes up, we welcome any discussion.
>
> As I mentioned earlier, our goal is to try and develop guidance for
> evaluating drug products to either slow or prevent myopia. Ultimately,
> any approvals that the Food and Drug Administration makes will be
> based on data. But in order to collect good data we need to have good
> trials.
>
> To date, as we have looked through, we believe the natural history has
> not been particularly well studied. Yes, there are some studies that
> go on for a couple of years but, since we believe this phenomenon goes
> on for a much longer period of time, we are not aware of good
> long-term follow-up, taking individuals and following them throughout
> the course of their life as opposed to cross-sectional data which we
> think there is lots of. There are also a great number of myths and
> anecdotal associations, some of which are bound to be completely valid
> and some of which are probably just myths.
>
> We note that refractive changes come from a variety of different
> sources. Some may be non-lens related and, as I say, we generally tend
> to think of them as occurring between birth through at least 30 years
> of age; accommodation related, which also occur starting at birth and
> go on generally up to about 65 years of age; lens related changes,
> which generally occur a little bit later in life, generally 40\--this
> is an arbitrary number\--but continue on until people either get a
> cataract removed or no longer have the need.
>
> We believe there are a number of potential influences of myopia.
> Listed on this chart are the two big categories that people tend to
> think of, genetics and environmental factors. Within environmental
> factors there are a number of subgroups. This is certainly not an
> all-inclusive list and part of the purpose of discussion today is to
> try and go through what people believe are the causes.
>
> When we are thinking about therapies, we expect that therapies may not
> necessarily be limited to directly affecting the disease process. By
> that, I mean we may know what the cause is and the therapy may be
> directed directly at what caused the myopia. There may be cases where
> we don\'t know what the cause is and therapies may or may not be
> directed because we don\'t know.
>
> We do not limit ourselves though to just therapies affecting the
> direct cause of myopia. For example, if the cause is that the eye is
> getting too long and we have a drug product that changes the shape of
> the cornea to compensate, that is acceptable. So, we are trying not to
> limit ourselves in the potential therapies but recognize we may either
> affect the direct cause or we may affect something that compensates.
>
> We recognize that as we try and develop protocols the issues will be
> complicated. They are complicated by things like genetics. They are
> complicated by the environmental factors; things that people believe
> are likely to affect myopia, either progression and/or things that may
> imbalance a particular trial. We expect those types of phenomena to be
> things like genetics, environmental factors like education, light
> exposure, refractive correction, work or play habits. These may or may
> not be factors and there may be additional things that we are not
> currently aware of.
>
> To start out with, I am going to try and start with the basics. The
> basics, from our perspective right now, are what is myopia? Who has
> it? Is all myopia necessarily bad? If not, is some worse than others?
> How long do we need to study it? How frequently do we need to look?
> And, how are we going to know when we have had a successful outcome?
>
> We have tried to translate these questions into more workable
> questions that we can deal with and, consequently, you have a whole
> long list of questions with many sub-parts. We expect that to occupy
> the majority of the day.
>
> But our goal is two things. Our goal is to have a discussion of the
> topic. That is equally important to answering the questions. So, the
> extent to which you can identify what we both know and what we don\'t
> know is important to the agency. As we go through the questions we
> would like to hear a consensus if one exists, but we don\'t believe
> that that is the end-all to answering any of the questions. If there
> is a range of answers, that is perfectly acceptable to us. We would
> like to know what that range and variety of different answers is; why
> you believe those particular answers; or if they are just hunches or
> if you would like to see that developed. Those are also things we
> would like to know.
>
> If we have not asked the right questions or if there are additional
> questions that we should have asked, please tell us. As I said, this
> is a beginning process. We think it will go on for some time. So, if
> there are other areas that you think we should be exploring, please
> let us know.
>
> Everybody has the questions in their handouts. I will go through them
> very quickly right now and then later on in the day we will
> specifically go through them point by point. These are the same
> questions that were in the background package although we have changed
> the order to them just a little bit to group things a little bit more
> appropriately.
>
> The first question is what is the minimum rate\--when we say rate we
> want both amount and time\--of a refractive change that determines
> whether myopia is classified as progressive, stable or regressing?
> These are probably the main categories of what myopia does. It either
> changes, stays the same or gets worse but we are not sure exactly how
> to define that.
>
> The term is sometimes used of high risk myopia, or people who are at
> high risk. To the extent that we can try and define what that group
> is, we are interested.
>
> Which population should be studied prior to approving a drug treatment
> for the prevention or retarding of myopia? We recognize that we can
> never study everything that we need to know about a drug product
> before we approve it. If we took the time to study every aspect of a
> product we probably wouldn\'t have these products in our lifetime. So,
> we think there is some kind of balance with benefits and risk. So,
> what we are trying to ask is what things do we think need to be
> studied prior to approving a product. For example, we have listed
> ages, education levels, ethnic groups, family history of myopia or
> other defining characteristics.
>
> If there is a minimum amount, what is that minimum baseline level of
> myopia for a multicenter set of associated factors that might justify
> a pharmacological intervention to arrest progression? Again, things
> like minimum axial length, minimum refractive error, minimum corneal
> curvature, and what period of time that needs to be observed over.
>
> What is the minimum amount of change that would justify a
> pharmacological intervention to arrest progression? If we decide that
> we don\'t want to look just at a baseline characteristic but if we
> want to look at people that are changing, what is the minimum amount
> of change that you would feel is necessary to answer those same
> aspects?
>
> Then looking at goals, what do we think the ideal refractive error is?
> Is there some ideal range? It may be emmetropia, it may be something
> else.
>
> How much of a refractive change is considered an important change for
> a particular individual? We have given a list of starting ranges of
> refractive error. This is tied to the earlier question, what should we
> be trying to get to if you start either at low ends of myopia or start
> at high ends of myopia? We have broken it down to a bunch of different
> categories. The answers may be the same for some of these categories
> or they may be different for every one of these but we are interested
> in your opinion.
>
> What is the minimum amount of change that would be considered a
> success if you are just trying to slow it as opposed to stopping it?
>
> Which are the clinically relevant, acceptable endpoints for
> myopia-induced ocular disease? These are diseases that we believe are
> potentially associated with myopia so if we were going to try and have
> a decrease in retinal tears because you believe that myopia is causing
> an increased risk in retinal tears, or decrease in retinal detachments
> because we believe there is an increased risk. Again, these are
> possible associations. We are looking at whether you think they are
> things that should be pursued.
>
> Then we go on to the different methods. How should the particular
> parameters be studied and measured? Do we think there are currently
> reliable, reproducible measures for assessing this in children? If so,
> what are they? We are looking for things potentially for refraction,
> both automated and cycloplegic; axial length measurements and the
> rest.
>
> Because we have heard a lot about high myopia being bad and how it
> affects someone\'s quality of life we would like to start addressing
> that early on. So, if there are particular ways of measuring quality
> of life, we are interested in hearing how you think that should be
> measured.
>
> Obviously, once we start doing these measurements we need to know how
> frequently to do the measurements. We don\'t want to do things that
> are overly burdensome but we want to do things that capture the
> information we need.
>
> The counterpart to how frequently do we need to do it, we need to know
> how long we need to do it for, both in testing durations of treatment
> and the follow-up that occurs afterwards.
>
> Obviously, a concern to us is having an effect, knowing what that
> effect is, looking to see if there is some kind of rebound associated
> with that effect and how long does it take to do all those things.
>
> There are a couple of safety questions that we have put at the end not
> because they are less important but just because we needed some place
> to fit them. One of the concerns has been in studying children that
> potentially have the risk for developing amblyopia. There have been
> concerns raised from time to time about whether it is appropriate to
> study children that are at risk of amblyopia and potentially altering
> their refractive error. So, we are putting that question just out on
> the table, is it acceptable to study children in that potential range
> or not?
>
> As we know, most drug products, in fact all drug products that I am
> aware or have some risks associated to them if they have any benefits.
> Those risks are frequently evaluated by looking at adverse events that
> occur. The frequency of adverse events is primarily dependent on the
> number of patients you study. If you study very few patients you are
> not likely to see relatively rare adverse events. So, we are looking
> at what is the frequency of adverse events you want to pick up in
> studying a particular drug product, recognizing that this is going to
> be directly correlated to the number of patients that need to be
> studied.
>
> Because we recognize that there may be some conditions that are
> probably considered more serious than others, retinal detachments
> probably being a more serious condition than general myopia, if those
> risks change because the condition gets more serious, we would like to
> know how that affects your answer too.
>
> Last but not least, if there are areas we have missed\--as I said in
> the beginning, we are most interested in the discussion that goes on
> so if there are additional comments, additional questions, anything
> else, we would like to hear that.
>
> Again, I want to thank you for your time and effort today in advance.
> Thank you.
>
> DR. GATES: Thank you, Wiley. Next we have a presentation by Dr. Ken
> Green, from Novartis.
>
> **Novartis Presentation**
>
> **Introduction**
>
> DR. GREEN: Good morning. I am Ken Green, with Novartis Ophthalmic. On
> behalf of Novartis Ophthalmic, I would like to thank the agency and I
> would like to thank this panel for organizing this meeting and for
> allowing us to be part of it.
>
> In the time allotted to us this morning we would like to cover the
> following agenda: After my introduction we will present three experts
> in the field of myopia research and they will cover a variety of
> topics, ranging from a discussion of natural history and prevalence of
> myopia, a discussion of the consequences of myopia to the patient and
> to the physician, and then a proposal of a clinical study design and
> an endpoint. Then I will finish with an overall summary.
>
> As part of the introduction, Novartis believes that the development of
> pharmacological treatments for myopia is important. We believe that
> patients and physicians continue to desire new ways to treat myopia
> and we would note, as an example, the significant rise in LASIK
> procedures in the past two years.
>
> There are two main impacts to a person who develops abnormal axial
> elongation, myopia and the refractive error associated with myopia,
> which is the immediate impact, and there are potential pathologic
> changes that Dr. Chambers referred to, which are long term.
>
> We specifically propose an indication for the treatment of myopia
> based on assessing the change in refractive error. It is not our
> intention to seek an indication for reduction in potential pathologic
> changes.
>
> Last year we were part of various discussions with the agency
> regarding study designs and endpoints for a pharmacological treatment
> for myopia. Those discussions culminated in a request to the agency to
> have this panel meeting so that we could get some clarification on
> some of these questions.
>
> Our primary objectives in our presentation are the following: We want
> to provide some background information on myopia, and we would like
> the opportunity to propose the rationale and study design for
> pharmacologic treatment for juvenile-onset myopia.
>
> With that, I would like to introduce the first presenter, Dr. Jane
> Gwiazda, from New England College of Optometry. Dr. Gwiazda?
>
> **Definition, Prevalence, Natural History and**
>
> **Risk Factors of Myopia in the U.S.**
>
> DR. GWIAZDA: I am Jane Gwiazda, from the New England College of
> Optometry. I am a Professor of Vision Science and I also am the Chair
> of the recently completed COMET study, which was an NEI-funded
> clinical trial investigating a spectacle lens intervention for slowing
> the progression of myopia in children.
>
> I am going to give a brief overview of myopia, definition and risk
> factors. I am sure most of you are aware of the condition that we are
> here to discuss today. Myopia is a refractive error where rays of
> light come to focus in front of the retina, mainly due to the eye
> growing too long. What this means for the patient is that he or she
> has blurry distant vision but can see clearly at near, hence the term
> near-sightedness that is commonly used for myopia.
>
> Juvenile-onset myopia occurs during the period from 6-16 years of age.
> What happens over this period is that the myopia progression is faster
> closer to onset and then, by the end of this period at about 15 or 16
> years, the progression is considerably slowed and in most children has
> stabilized.
>
> You should note that this definition does not include any mention of
> potential pathologic complications of myopia. This figure just
> demonstrates that the myopic eye is longer, oval shaped, and a point
> source of light comes to focus in front of the retina, whereas in the
> normal emmetropic eye the point source comes to focus on the retina.
>
> Levels of myopia are often defined in this way, low, 0.5 to less than
> 3 diopters; moderate, between 3 and 6 diopters; and then high or
> severe myopia would be anything over 6 diopters. You should note that
> in this presentation these definitions may change because they are not
> always used by all studies.
>
> The most commonly cited figure for the prevalence of myopia in the
> United States, even though these data are now\--well, they were
> published 20 years ago and they were collected 30 years ago but they
> are still being cited. These are from Sperduto et al., the NHANES
> study. The prevalence between 12-54 is 25 percent. You can see that
> there is more myopia in women than in men. There is also more myopia
> in whites than in blacks.
>
> If you look more closely at these data, you can see that the lower
> levels of myopia, either less than 2 diopters or between 2 diopters
> and 8 diopters, are much more prevalent than the high myopia where we
> only have a prevalence in this study of 0.2 percent.
>
> Turning to the progression of myopia, a number of studies have shown
> that in Caucasian children, during the period when myopia is
> progressing most rapidly, the annual progression rate is approximately
> 0.5 diopter per year. For children in Asia, many studies have shown
> that the annual rate of progression may be up to twice as great.
>
> These are data on progression of myopia in the COMET children. COMET,
> as I mentioned, was a study to investigate a spectacle lens treatment,
> that is, progressive addition lenses as compared to single vision
> lenses, which is the standard treatment for myopia in slowing the
> progression of myopia in children.
>
> We enrolled 469 children. They were randomized to one of these two
> lens types. Their mean age at the start of the study was about 9.5
> years, and their mean myopia was close to 2.5 diopters at the start of
> the study. So, what I am showing here are data from the children who
> wore the single vision lenses, starting at baseline when their myopia
> was around 2.5 diopters. On average, in the first year their myopia
> progressed 0.6 diopter; in the second year, 0.5 diopter; and in the
> third year, 0.4 diopter. So, this is how we get the average of 0.5
> diopters per year from the COMET data.
>
> We are continuing to follow COMET children so we will, in five years,
> actually have data showing what happens to progression beyond the
> first three years. Right now, we have extrapolated out three
> additional years, conservatively estimating that the progression will
> slow by 0.1 diopter per additional year. So, when you get out six
> years, the progression of myopia is slowing down considerably, if not
> stabilizing, in most children.
>
> We also know, and this may seem obvious, that if a child has myopia
> starting at a younger age, by the time the myopia progression is
> stopping that child is going to have more myopia. These are data from
> Mantyjarvi, et al., in Finland. What they show is that if the onset of
> myopia is at about 7-8 years of age, those children at 15-16 years of
> age have five times as much myopia as those children whose onset is at
> 15 years of age.
>
> Turning to risk factors for developing myopia, Dr. Chambers has
> mentioned both genetic and environmental factors, and I certainly
> believe both are involved and there is a complex interplay between the
> two. What we show first is that there is a strong association between
> myopia and parents with myopia and their children. These are data from
> Mutti et al. in a recent study. I have similar data from my own
> laboratory. What they show is that if a child has two myopic
> parents\--these are children who are 13-14 years of age, the
> prevalence of myopia is 33 percent. With one myopic parent, it is
> reduced to 18 percent. If neither parent is myopic, it is only 6
> percent. You can see that the odds increase with increasing numbers of
> myopia parents.
>
> We also know from a study in Singapore, and I also have some data in
> my own laboratory showing that number of myopic parents is not only a
> risk factor for developing myopia, it also is a risk factor for
> progression of myopia. So, there is greater progression in children
> with one or two myopic parents compared to zero.
>
> I really don\'t have time to get into the environmental factors today.
> The one that is most commonly cited is near work activities in
> children, but there are many others that are out there in the
> literature.
>
> To summarize, the key points are that myopia is found in at least 25
> percent of individuals in the United States; that the lower levels of
> myopia are much more prevalent than the higher levels. The mean
> progression in Caucasian children is approximately 0.5 diopter per
> year. Earlier onset of myopia in children results in higher levels by
> the age of 16 when myopia progression is slowing. And, the risk of
> developing myopia is related to both genetic and environmental
> factors.
>
> Now I would like to introduce Dr. Joe Miller.
>
> **Consequences of Myopia**
>
> DR. JOSEPH MILLER: Thank you. My name is Joseph Miller. I am a
> pediatric ophthalmologist at the University of Arizona, and a
> professor in the Departments of Ophthalmology at the Optical Sciences
> Center and in our College of Public Health.
>
> As far as my research background, I am a practicing pediatric
> ophthalmologist and I carry with me the perspective of a practitioner
> who takes care of children and consults with the parents of those
> children. I am an NIH-funded investigator, researching the effect of
> astigmatism on visual development of native American children. With
> regard to myopia, I am an investigator in the CLEAR study and,
> finally, I serve on a data monitoring and oversight committee for
> early treatment of retinopathy of prematurity, a disease which has a
> very strong association with myopia. So, I have some research
> experience with myopia.
>
> Pertinent to this study, however, I was also an investigator in the
> pirenzepine 205 study, PRI 205, and I was on the planning board for
> that and, additionally, served on the planning board for the amblyopia
> treatment study number 1, which was the atropine study that
> demonstrated the use of atropine as an effective and safe alternative
> to eye patching. So, I am not a myopia maven in the sense of people
> who do animal research, but I am a clinician who works in the area and
> a scientist who works in the field.
>
> What I would like to do is to try and break this into two different
> categories, the implications if you have myopia as far as the risk of
> other eye diseases and then from the perspective of the patient or the
> child who has myopia, what are the effects of that myopia in terms of
> the induced refractive error and the eye changes in terms of how they
> see.
>
> Well, first off, in order to get to what the effects of myopia are on
> the eye, it is worthwhile remembering that when we are talking about
> myopia we are talking about light not falling in focus on the retina.
> That can occur from one or two reasons. Either the optical power of
> the anterior segment of the eye is too great, causing the light to
> fall into focus prematurely in front of a normal eye in terms of axial
> length, or you can have an eye which has a \"normal\" optical power in
> its anterior segment but there is too long an eyeball and axial
> elongation present, resulting in the light falling into focus an
> appropriate position for a normal eye but in the case of a myopic
> individual the eye is too long and the light falls into focus ahead of
> the retina, or it can be a combination of the two, resulting in some
> sort of mismatch between the two.
>
> We talk about myopia in units of diopters. There are lens equations
> that describe what a diopter is but, for the purposes of this
> discussion, the basic rule of thumb is that about 2.67 diopters is the
> difference of 1 millimeter in axial length. In measurement of axial
> length there are ways that this can precisely be measured either with
> light refraction measurements, ocular coherence tomography, or partial
> coherence. There are also ultrasound measurements so we can measure
> the length of the eye. We can measure the power of the anterior
> segment of the eye, particularly the cornea. We know the shape of the
> cornea quite precisely. But clinically the defining characteristic of
> myopia is a procedure called refraction where various lenses are
> placed in front of the eye and adjusted until the light for that
> individual patient falls in focus on the retina.
>
> So, the types of data that we are able to collect from people who have
> myopia are related to the length of the eye, the optical power of the
> eye and where the light needs to be adjusted in front of the eye in
> order to fall into focus on the retina.
>
> As this eye grows things can get out of balance and the disease which
> we call juvenile-onset up seems to be characterized by an abnormal
> rate of growth of the eye itself. Axial elongation seems to be the
> defining characteristic of juvenile-onset myopia, the predominant form
> of myopia that we are discussing today.
>
> If you have an eye which was originally intended to be this size and
> it grows to be bigger because the sclera, the white part of the eye,
> is growing and the inside lining of the eye, the retina, does not grow
> to keep up, then what happens is that the eye becomes stressed in a
> fragile tissue. The retina itself has the strength and consistency of
> about wet tissue paper, whereas the sclera is much more expansible and
> can grow. So, as the eye grows one of the consequences of myopia is
> that changes occur in the retina. Initially stress results in
> stretches, in tugs and pulls leading to myopic degenerations. Finally,
> if those stresses are exceeded, catastrophic failures can occur such
> as retinal detachment.
>
> Frequently also cited in the literature in textbooks, besides these
> retinal associations, is that glaucoma is associated with progressive
> levels of myopia.
>
> Let\'s first talk about myopic retinopathy. Myopic retinopathy is the
> condition, as I mentioned, where the retina has been tugged and pulled
> and there are various changes that occur. Typical names are lacquer
> cracking that you see referred to as a characteristic. What happens is
> that the retina is stressed and little tears develop or where the
> retina is attached, it becomes stressed in those locations. This is a
> very common condition among people with advanced levels of myopia, for
> sure. If you have 9 diopters of myopia or about 3 millimeters of axial
> elongation, over half of those people show these degenerative changes
> in the retina.
>
> But what surprised me when I reviewed this literature is just how
> common it is in moderate levels of myopia. In the 3-5 diopter range we
> find that just slightly less than 5 percent of the people show these
> changes. So, this is a very prominent and very common finding among
> people with myopia.
>
> Fortunately, much less common is the event of retinal detachment. In
> the general population about 1 person in 20,000 will experience a
> lifetime risk of retinal detachment developing. These papers are
> cited, the Eye Disease Case-Control Study Group and a paper from Japan
> by Ogawa, et al. that reviewed the risk of retinal detachment
> developing as compared to levels of myopia, case-control studies, if
> you will.
>
> These have been reevaluated as univariate odds so that we can compare
> them. What is striking to me is across continents how similar these
> numbers are in terms of what happens to people who have progressive
> levels of myopia.
>
> This number of 3.87, 3.81 or about 4, please don\'t interpret that as
> meaning that one person in four develops retinal detachment. That is
> not what these numbers mean. Retinal detachment is a rare event, but
> what it does mean is that if you are a practicing ophthalmologist and
> someone comes into your office with a retinal detachment, that person
> is four times as likely to have that retinal detachment if they
> exhibit low myopia compared to the condition called emmetropia where
> the optical power of the eye is in balance with its axial length.
>
> At moderate levels of myopia the risk of being associated with myopia
> increases to about 10-fold. In the Ogawa paper, where they further
> stratified people into having 6 diopters or more of myopia the odds
> ratio increases to 26-fold elevation of risk for 6 diopters or more.
>
> The perception of many of us in the practicing ophthalmologic field is
> that myopia is associated with disease. But from the perspective of
> the patient, myopia is associated with a problem of seeing things far
> away, and if you can get closer to things you can see them more
> clearly. People also associate it with the need for wearing eyeglasses
> or some other correction. They often associate it as well with a
> certain point in their life. They can remember when they started
> having trouble seeing things, or the experience in the classroom that
> led them to say something about it that led to them ultimately
> receiving eyeglasses. So, there is a definite relationship as well
> between the amount of the myopia that is present and visual
> impairment.
>
> A standard textbook, Bennett and Rabbetts \"Clinical Visual Optics,\"
> has a nice table in it that I have adapted here that relates the
> amount of myopia present with the expected level of uncorrected visual
> acuity and the number that we use in analysis of data, the logMAR, in
> terms of how much myopia is present and how well we see. So, these
> numbers are the Snellen fractions that we normally think of when you
> go to get a driver\'s license, and 20/40 vision is what we use as a
> cut-off for being able to see in most states for getting a driver\'s
> license. That number is associated with 0.75 diopter of myopia.
>
> If you have ever had your eyes checked and you have sat behind that
> machine called a foropter and the doctor is flipping back and forth
> with those knobs, each click of that knob is 0.25 diopter on the
> sphere dial. One of the things that we learn very early as clinicians
> is that when you are refracting someone and you are trying to refine
> their refraction and intentionally make their vision blurry by giving
> them too much plus power, effectively making them a mope, for each
> click of the knob they should give you back one more line of visual
> acuity and improvement.
>
> So, this is a clinical rule of thumb that I think clinicians learn
> very early in their practice but as far as what the literature is to
> support this, actually there is really quite a bit that has been
> studied. One of the best papers I think to look at this was by Maj.
> Pincus, given a task to evaluate the relationship between refractive
> error and unaided visual acuity. The reason for this study was quite
> simply that people were trying to get into the service and claiming
> that they had better vision than they actually had. So there was this
> condition called positive malingering that was an issue.
>
> Over 7,000 cycloplegic refractions went into this data set in which
> the individuals had a cycloplegic refraction; they had an unaided
> visual acuity and everybody that was in the study had a best corrected
> visual acuity of 20/20 or better. Each of the data points that you see
> here is an average of a large number of individuals. So, at a given
> level of refractive error, sphere and cylinder, the average acuity was
> calculated from that 7,000 value.
>
> What I have done is taken that data set and extracted from it the
> individuals who had 5 diopters or less spherical equivalent myopia and
> 1 diopter or less cylinder, and plotted them against the more modern
> scale, which is logMAR acuity. Across the bottom is spherical
> equivalent refractive error. There is a very striking linear
> relationship that you can see here. If you have 0.75 diopter of myopia
> you are in a cluster over here that is 0.3 logMAR units, or 20/40. If
> you double the amount of myopia from 0.75 diopter to 1.5 diopters, you
> are sitting at 0.6 logMAR, or 20/80. As this linear scale continues it
> starts to flatten out at higher levels of myopia.
>
> That is a bit of data about numbers but as far as how people see with
> myopia, to try and give you an idea of what that actually looks like I
> turned to my colleague, Jim Schweigerling at the University of
> Arizona. Dr. Schweigerling is an optical scientist in our department
> and our department has developed an eye model, a computerized eye
> model that includes such factors as pupil size, axial length, the
> pupil function and is an exact rate trace model that is based on the
> standard eye.
>
> So, what these computer simulations are trying to demonstrate is to
> give you an idea of what an uncorrected myope would see without
> wearing their glasses. As they take their glasses off, this is as best
> we can build a model of what the vision looks like in terms of both
> blur, in terms of contrast sensitivity and, finally, this is a single
> average pupil size but it is important to remember that in real life
> our pupils get bigger and smaller. So, our actual vision is sometimes
> worse or sometimes better depending upon whether the light is very
> bright and our pupil is small or our pupils are large. But this is the
> best that I think we are able to do under the current state-of-the-art
> in actually estimating what it is people see and perceive.
>
> I think the first thing that you will see is that for uncorrected
> myopia of 5 diopters you have a hard time seeing what those things
> hanging up on those trees are. They are called leaves. I had a
> resident that I was with that kicked them around until first grade and
> didn\'t know they are associated with trees because he had 9 diopters
> of myopia and didn\'t know it until he got to first grade.
>
> The second thing that I think you will see is that if you are
> comparing the pictures in the center column to those on the right,
> this picture looks more like this picture than it does like this
> picture. I mentioned that at higher levels of myopia the visual
> degradation starts to flatten out. We become less and less sensitive
> to blur in our brain with higher levels of myopia than with lesser
> levels of myopia.
>
> One of the things that I think is pretty clear is that at these very
> high levels, if you don\'t have an optical correction on, you are
> severely disadvantaged and you wouldn\'t be able to do much beyond act
> in a Mr. Magoo cartoon. The people that are walking with 7.5 diopters
> of uncorrected myopia, they may be able to find where the open door is
> to get out of a room but they are severely disabled in terms of their
> vision and these are people that tend to wear their correction all the
> time.
>
> On the other hand, as you move to lesser amounts of myopia, lesser
> magnitudes, at 2.5 diopters of myopia you can recognize that the tree
> has leaves and you might be tempted to go skiing without wearing your
> correction.
>
> But it is important also to remember that myopia is characterized not
> by fixed poor vision at all distances, but people who are myopic see
> things up close better than they see things further away. So, the
> child\'s visual environment, as the child develops myopia, is
> something that they can manipulate. If they are able to get up and
> move closer to the object of regard, the thing they are trying to look
> at, they will do so.
>
> So, let\'s think of this in terms of the perception of a child who is
> perhaps starting to develop myopia and is now starting to experience
> what is going on in terms of not being able to see clearly in the
> distance but perhaps better at near.
>
> Here is a simulation of a child trying to find a friend in a crowd.
> The child is modeled as having 3 diopters of myopia. These children
> are assumed to be 20 ft away for the purposes of this simulation, and
> our task as observers is to try and identify our buddy, Waldo, across
> the field. So, this is sort of a \"Where\'s Waldo\" game. At 3
> diopters of uncorrected myopia you are going to have a hard time
> spotting your buddy. It is actually, I think, kind of hard to know who
> is a girl and who is a boy in this crowd. Unless you know what it is
> your friend is wearing you would probably run into problems. Three
> diopters of myopia is associated with an expected visual acuity of
> 20/320. The best corrected vision of 20/200 is legal blindness so if
> you are not wearing your glasses you would be in the range of visual
> acuities that are called legally blind.
>
> As we decreased this by 0.75 diopter to 2.25, you can see a dramatic
> improvement in terms of what the child is able to see. You are
> starting to recognize who is a boy, who is a girl and it starts to pop
> out at you that this is probably Waldo over here. But, certainly, no
> details about these children are clear. You don\'t know whether the
> child is smiling at you. You certainly can\'t make eye contact.
>
> At 20/80 vision you start to see things that I would consider to be
> details. You can see that some of these children are smiling. You see
> the body language that is going on here. One guy is leaning on another
> guy. The second thing that becomes apparent at this level of myopia,
> if you are clinician, is that there are an awful lot of kids that come
> in and get their first pair of glasses at this level of myopia. A
> pretty common first prescription for glasses is in the minus 1.5 to
> minus 1 diopter range. That is when a child finally shows up in your
> office. So, there are an awful lot of kids who develop myopia and have
> it for a while that are running around like this. It leads me to think
> that many kids then tolerate this level of myopia because they
> haven\'t started complaining yet or it hasn\'t become so apparent yet
> to their parents that they know something is wrong.
>
> Let\'s decrease this by another 0.75 diopter, down to 0.75 diopter. We
> are now at a 20/40 level of vision. This is the level of vision that
> you are expected to have to drive a car uncorrected. Really quite a
> bit of detail is now apparent. You can see the buttons on the
> children\'s shirts. You can see the smiles. You are going to get the
> social clues that are going on.
>
> But what I do want you to look at right now is the overall image
> quality that we are seeing here and compare it to this image, which is
> no refractive error. For me, the biggest thing that I see different is
> the loss of contrast that someone with a small amount of uncorrected
> refractive error experiences. We hear this message taught to us over
> and over again by patients who are refractive surgery patients when
> they learn that visual acuity is only one component of how well we
> see. How far you read down on the eye chart is just one point in our
> visual function and contrast sensitivity is an important measure.
>
> So, the overall image quality when you have myopia is not just
> impacting how far down the eye chart you can read, but also how well
> you perceive other things, how bright the bright colors appear to be.
> You hear this from people when they get a new pair of glasses, that
> things look crisper, brighter.
>
> The other thing that I would mention is that very often the difference
> between here and here is what brings people back to the office to get
> a new pair of glasses. The 0.75 diopter change is a typical number
> that you see being used when clinicians decide whether to give a new
> prescription that is slightly stronger.
>
> That is the perception from a distance task. You could argue that the
> child, if they really wanted to know what was going on, could walk the
> 20 ft and see what is going on. But if you are a kid in the classroom
> and you have already been moved to the front of the class and you are
> sitting in the first row, it is a little different.
>
> This is a simulation of a child at the blackboard. This child is now 6
> ft away from the blackboard. What we are trying to do is look at what
> happens here to various levels of visual acuity and associated levels
> of myopia. In terms of how well the child reads the eye charts, this
> is the eye chart at 20 ft, a logMAR chart, and this is the child in a
> classroom looking at a friend at the blackboard and trying to read the
> blackboard.
>
> If you are sitting up close, I think the first thing is that even at
> 20/160 vision you can see the blackboard and if the teacher has
> written large and clearly and you have a blackboard that is using
> white chalk against a dark background you can make out these numbers
> even with 2.25 diopters of uncorrected myopia. Unfortunately, I think
> nowadays the more typical complaint I hear from students is that the
> teacher is using an overhead projector with a dried out fuchsia
> colored marker, and the contrast is terrible and they can\'t see in
> the classroom even with relatively low levels of uncorrected
> refractive error.
>
> So, despite the fact that we are in this range of 2.25 diopters of
> myopia and at 20/160 vision, you can understand how some children sit
> in the front of the class or get moved to the front of the class and
> still function. Is this ideal or desirable? I would submit not.
>
> We now have moved by 0.75 diopter to 1.5 diopters and it is a
> three-line jump on the visual acuity chart. We are now looking at a
> line and able to resolve a line that is half the size it was before.
> You can see a big improvement in how well the blackboard is seen.
> Again, 1.5 diopters of myopia is a level of myopia with which a lot of
> kids participate in sports without correction. A lot of kids will be
> advised to take their eyeglasses off for playing soccer. So, you are a
> kid, you are out on the playground a lot of times, running around
> without your glasses on and this is sort of the expected level of
> vision if you have 1.5 diopters of myopia.
>
> We now jump to 0.75 diopter of myopia which, again, sounds like a very
> small amount but it is in that range of 20/40 vision. The details
> really are quite apparent. You can start to make eye contact if you
> are sitting in the front row. The numbers are legible if the teacher
> is writing big. If you move into the upper grades, however, the
> material in classroom work becomes smaller and more difficult. If you
> are holding it up close you are going to be able to see it but if it
> is far away and you can\'t change where you have been seated, you are
> going to have problems.
>
> Lastly, let\'s look at the fully corrected child or the child who has
> no refractive error. They see all the way down to the 20/20 line on
> the eye chart. Things are sharp and in focus. But now let\'s think
> about this as a slightly different thing, what if you are a child who
> is, say, 3 diopters myopic and you have worn those glasses for a while
> and the glasses are only correcting 2.25 diopters of your myopia? So,
> you are under-corrected by 0.75 diopter. If you had your full strength
> glasses on, this is what it would look like. But if you have those
> glasses which are not strong enough by 0.75 diopter, this is what the
> world would look like.
>
> So, these simulations can also be scaled back for wearing lesser
> amounts than the full correction to give you an idea of what the child
> is perceiving if they are not wearing their glasses and they are not
> fully correcting the problem at hand. So, as best we can tell, with
> the exception of a small effect in terms of making the overall world
> seem smaller, one of the effects of wearing a high optical correction,
> if you have ever looked at someone who is wearing a myopia pair of
> glasses, their eyes look small when you look at their face through the
> glasses. The same thing happens in reverse. As they look at the world,
> the world becomes minified. With the exception of this minification
> effect, these same numbers can be applied to trying to estimate what
> the effect of under-correction is in a child\'s vision.
>
> So, I tried to give you an idea of what the visual perception is of
> these children who are having a level of myopia. What I hope I have
> demonstrated to you is that there is a real, appreciable difference
> that is associated with this doubling of the visual angle. A doubling
> of the visual angle means that each time that we jump up by three
> lines the line becomes twice as large in terms of the eye chart. But
> not just how well a child can read an eye chart, it translates into
> real and significant effects in terms of how they perceive the world,
> not just in terms of how fine a detail can be resolved, but in how
> sharp and crisp and clear the image is.
>
> This 0.75 diopter progression is a value that is supported in the
> literature. It is a value that has been drilled into us from the first
> day of refracting. And, it is a number that seems to have both
> clinical and statistical significance.
>
> This is an idea, I hope, as to how the children with myopia see but
> now let\'s turn it into the perception of the parent who is bringing a
> child in who can\'t see because they have been moved to the front of
> the class and they are already sitting in the front row, and finally
> the message gets across that the child needs a pair of glasses. So, I
> am moving back to the position of being an eye doctor and I have a
> child sitting in front of me. What are the options that I have to
> offer a child who has myopia?
>
> Well, these options are listed in I think roughly increasing levels of
> risk for that child, and probably in terms of convenience or desire of
> 13-year old kids to have the reverse list. But single-vision glasses
> are the cheapest, the easiest way to correct somebody\'s myopia. They
> are safe if you are not hit by a soccer ball. They are very effective.
> Single-vision lenses are inexpensive and they are widely used as the
> primary treatment for refractive error.
>
> Contact lenses\--I think really the first three in this category are
> different than ortho-keratology, which is a procedure where the cornea
> is being remodeled to a shape that changes the front power, the
> optical power of the eye in order to bring the light into focus at the
> appropriate place. So, this is a contact lens procedure but its goal
> is to reshape the cornea.
>
> Finally, are refractive surgery options for when the children are
> older, and in some places in the world are actually being offered to
> younger children now.
>
> This list gets old after about the second or third time the parent has
> brought the child in to see me for a stronger pair of glasses, and it
> doesn\'t take long before I get asked the question, \"Doctor, isn\'t
> there anything else you can do to keep this from getting worse?\" Then
> I bring up my little spiel about, \"well, we have some options. Some
> have been investigated.\" When I talk about what those options are I
> start with you can save the old pair of glasses and you can wear those
> glasses in the evening to read with, intentionally under-correcting
> the child at near. I talk about the COMET study and the addition
> lenses that have been used, and relate the fact that I put both of my
> kids in progressive addition lenses when they were younger and that
> their myopia stabilized, but then I point out you look to me like you
> are really quite myopic and neither my wife nor I are. So, I don\'t
> know whether they didn\'t progress because they weren\'t genetically
> predetermined to or because the PAL lenses worked. But the kids like
> the lenses. Because they didn\'t have a line they were acceptable to
> the kids and they wore them, or at least they told me they did.
>
> Rigid gas permeable lenses, the thinking here is, rather than ortho-K
> to reshape the cornea, this is to stabilize the cornea to its present
> shape. As I said earlier, however, juvenile-onset myopia is
> characterized by axial lengthening more than changes in the optical
> power of the eye. So, I am not sure how that is going to play out.
> Certainly, in terms of studies the amount of data in good studies,
> talking about RGP lenses to control the progress of myopia, is lesser.
>
> That leads me to pharmacologic treatments. I talk about the fact that
> in various parts of the world, various things have been used to
> various extents. The one thing that we know is that atropine is very
> effective at slowing or stopping the progression of myopia. But the
> problem with atropine is its side effects. The very same side effects
> that make atropine so undesirable to put in both eyes to use for the
> treatment of amblyopia are those side effects that we went after to
> use atropine as a penalizing method in the treatment of amblyopia. Its
> effect is to paralyze accommodation and widely dilate the pupil. You
> can give that child a pair of bifocal glasses to wear and the child is
> able to see at all distances, in theory, well but it is instantly
> making that child as presbyopic as you would be if you were 55 years
> old. Just as happy as you were to get your first pair of bifocals,
> these children are when they become dependent upon bifocals with
> atropine.
>
> That is the first effect. The second effect is the huge pupil that you
> get from atropine. The larger the pupil size, the more aberrations
> enter the eye and the image quality degrades to some extent even if it
> is fully corrected with spectacle.
>
> The last issue about atropine is that, because the pupil is so large
> and unresponsive, the light seems to be very bright and the child is
> often faced with glare problems when they are outside playing. In the
> amblyopic treatment study we advise children to wear hats and
> sunglasses as appropriate and we always place the child in ultraviolet
> blocking lenses in order to try and protect the child against these
> side effects.
>
> But one of the things that I strongly believe is that if we are going
> to have an effective pharmacologic treatment it has to be a medicine
> that does not carry with it the side effects of atropine. Because even
> though atropine has been available off-label as an effective use for
> slowing the progression of myopia, it is very seldom used because the
> side effects are so profound.
>
> That leads me to where I am today, which is requesting that we find a
> way to develop a safe, effective and approved medicine that can be
> used in slowing the progression of myopia. I would like to have an
> option to offer these parents who come to me and say I don\'t want my
> child to be as myopic as I am. I don\'t want my child to need to have
> stronger glasses each time.
>
> So, in order to discuss issues around such a design of a trial, I
> would like to introduce my colleague, Dr. Karla Zadnik.
>
> **Proposed Clinical Study Design**
>
> DR. ZADNIK: I am Karla Zadnik, from the College of Optometry at Ohio
> State University. I have chaired first a single-center and then a
> multicenter study of the development of refractive error in children
> since 1989.
>
> In the spirit of jump-starting or giving a beginning place for the
> discussions as Dr. Chambers outlined\--that is a pretty lofty
> agenda\--what we would like to do is present a proposed study design.
> It hits on many of the issues that Dr. Chambers introduced. It
> probably also introduces a couple of other issues. So, that is really
> the purpose of my presentation.
>
> The proposed indication that, in representing Novartis, I am proposing
> is that a pharmacological agent be looked at to reduce myopia
> progression in children diagnosed with juvenile-onset myopia. So,
> those are the children already with myopia of a certain degree, as you
> will see.
>
> This is perhaps analogous to the approved indication on the devices
> side of the house for refractive lasers, which reads, \"for the
> reduction or elimination of myopia,\" but it is not an indication that
> would claim or promise to have any demonstrated effect on whether a
> child would develop retinal findings in their 20s or retinal
> detachment in their 40s, nor would it claim to reduce the risk of
> those things happening to that person in the future.
>
> So, a study design to put on the table is a prospective one. The
> children would be randomized to the study treatment or to placebo. It
> would be double-masked and conducted in an appropriate fashion.
>
> The time period is a huge issue. It was raised early this morning, and
> we would propose 30 months on drug to establish the safety and
> efficacy of that agent. That is a time period that we arrived at
> because it resonated with clinicians that we spoke to. It also exceeds
> international regulatory guidelines and would be longer than the usual
> in terms of assessing the safety of something that would be used in
> children specifically.
>
> There would be also a 6-month off drug period to address the potential
> for what has been termed a rebound effect. I am sure there are lots of
> ways we could think about rebound for an agent like this that would
> retard the progression of myopia in some way. I think rebound would
> not be that the child went off drug and the myopia progression resumed
> as would have happened to the child at the age he is at that time. So,
> that would not be a rebound; it would just be he is off drug so the
> drug isn\'t working anymore. Rebound would be if the eye growth
> accelerated to make up for the period of time that a child had been on
> treatment. That sounds like a rebound effect for a drug like this.
>
> Lastly, the number of subjects, the sample size, would be determined
> to detect adverse events at the one percent level. I think one of your
> discussion points is whether that would be sufficient for a study of
> any agent that might be used in children.
>
> So, for proposed study entrance criteria the children would be 6-12
> years old at the time that they entered the study and they would have
> myopic refractive error ranging from 1-4 diopters as measured by
> cycloplegic auto refraction and specified by the spherical equivalent
> component of their refraction.
>
> They could have 1.25 diopters of astigmatism in either eye, and they
> could not have anisometropia as much as a diopter that is a difference
> between the eyes. They could not have strabismus or eye turn, and they
> would have to be able to see well with their spectacles on. So, their
> best corrected visual acuity would need to be at least 20/32 in each
> eye. It would seem obvious that you would rule out any children who
> had any ocular or systemic or neurological conditions that would be
> known to affect growth of the eye or refractive development.
>
> One issue is what would be the outcome of a study like this. What
> would be the things that you would want to measure, and what would be
> the measurement that you would hang your hat on? Well, it seems fairly
> obvious that if the indication were to slow the progression of myopia
> the primary outcome would be the progression of myopia. One of the
> issues is how to measure that in children. I think we could all argue
> that cycloplegia and paralyzing the ability of a child to accommodate
> during the measurement would be important to stabilize that measure.
> Many studies have investigated whether subjective refraction or auto
> refraction or other methods that one might use are appropriate.
>
> I think auto refraction has sort of come out the winner out of
> previous studies. All the child has to do, even a 6-year old, is just
> to sit there, face in a chin rest. They wiggle a little but they can
> do that pretty well. It also allows you to get multiple measures. With
> an auto refractor each click of a button is equivalent to the whole
> refraction procedure that you go through when you answer which is
> better, one or two, over and over and over. So, you can take 10
> measurements on a child very quickly which gives you the ability to
> improve your repeatability with multiple measures. So, I think auto
> refraction under cycloplegic conditions is probably the most
> repeatable, most reliable and valid way to measure refractive error.
> Then, that progression of myopia would be specified as the change from
> the baseline refractive error that the child had when he or she
> entered the study.
>
> For any pharmaceutical agent that purported to slow the growth of the
> eye, that is, one that affects the underlying cause, you would want to
> measure the axial length. That seems fairly obvious. But I can imagine
> that secondary outcomes might be different for pharmaceutical agents
> that proposed to have a different method of action. If you were
> proposing to somehow change the shape of the cornea in a way that
> would be acceptable in children then, obviously, corneal curvature
> would be an important thing to measure. But for the purposes of one
> that really did slow this abnormal growth of the eye, axial length
> would be an appropriate and logical secondary outcome measure,
> measured in a repeatable fashion.
>
> Now, one thing that we have really wrestled with is what would
> constitute for any agent a clinically important, meaningful change to
> children, to parents to clinicians. So, we have sought feedback and
> tried to put that story together from a variety of ways, one of which
> is direct feedback from eye doctors\--what do you think is a
> significant reduction in the myopia progression? Dr. Miller presented
> the idea that there can be some logical correlation to change in
> uncorrected visual acuity.
>
> Lastly, there is just a hint of beginning data on quality of life in
> patients who are myopic as it relates to the magnitude to their
> refractive error.
>
> So, when we have convened some advisory panels of clinicians, both
> internationally and in the U.S., what they tell us is that a change in
> refractive error for them of 0.5 diopter to 0.75 diopter is clinically
> meaningful to them. So, we can talk about that when they change
> glasses on a child, but that seems to be a number that we keep hearing
> from clinicians.
>
> Dr. Miller presented that doubling of the visual angle correlates well
> with a 0.75 diopter change in refractive error and gave you a very
> visual idea of what it would be like to double your visual angle over
> and over and over as your myopia worsened. That change in visual
> acuity that corresponds to that doubling of the visual angle has been
> accepted in ophthalmic drug trials in the form of best corrected
> visual acuity and in device trials in the form of uncorrected visual
> acuity.
>
> I think one thing we perhaps have come to realize with the advent of
> and popularity of refractive surgery is that maybe uncorrected visual
> acuity is a lot more important to our patients than we ever though. As
> eye care practitioners, we are in the business of putting something on
> people and making them see well, but what we find is that patients
> tell us I care quite a bit about whether or not I can see the alarm
> clock, or when I stay in a hotel I have to know where my glasses are
> on the nightstand in case there is a fire so I can make it out the
> door. So, based on these criteria, this sort of brought us to this
> 0.75 diopter change as being clinically significant.
>
> On the topic of quality of life, there are a variety of groups that
> are now working in the development of quality of life instruments that
> are specific to refractive error. They attempt to measure whether a
> patient reports a better quality of life on this questionnaire if they
> wear contact lenses instead of glasses or if they have refractive
> surgery instead of wearing spectacles or contact lenses. One of those
> is the Refractive Status and Vision Profile, out of John Hopkins
> University. It has been validated and it is the only group whose
> device and testing of that device has matured enough that there is
> actually published data.
>
> So, this particular paper by Susan Vitale reports on a cohort of 550
> people who have mostly myopia and no previous refractive surgery, most
> of the sample, and then a small portion of the sample at least three
> months past their refractive surgery.
>
> What they found was that for each additional diopter of myopia that
> the person had, they were significantly more likely to say they were
> dissatisfied with their vision. So, there was a relationship between
> higher, increasing myopia and saying, \"I\'m not really very happy
> with the way I see,\" on this particular questionnaire.
>
> Now, an issue that I don\'t think was raised at the beginning of the
> morning that I am going to put on the table for discussion is that in
> studies like this there is an issue of how to analyze the data. I
> don\'t promise to be a biostatistician but let\'s see if I can outline
> this for you.
>
> One is to simply analyze the difference in the mean progression of
> myopia in the treatment group compared to the placebo group, and
> statistical significance would tell us that the mean change from
> baseline was significantly less in the treatment group. That is one
> way to do it.
>
> In addition, this clinically meaningful difference comes into play
> because it would be important that the observed difference between
> those two means of the two groups would be clinically meaningful. So,
> that is where this 0.75 diopter idea comes along.
>
> An alternative way to analyze data like this, whether it is in a
> myopia trial or in any clinical trial, would be to say what we are
> really interested in, or one way to analyze the data would be to say
> we are going to take that clinically meaningful amount and we are
> going to look at the proportion of children whose myopia progresses by
> that amount or more and compare those proportions between the
> treatment group and the placebo group. A statistically significant
> result would be if the treatment group had fewer children, a smaller
> proportion, who had progressed by that prespecified clinically
> meaningful amount\--the same data set but two different ways of
> approaching it statistically.
>
> As think about all of these things put together, what we would like to
> do is recommend a primary efficacy variable as follows: Number one, we
> have told you from different approaches and by some visual displays
> that we believe a change of 0.75 diopter would be clinically
> significant. But from some previous discussions over the last couple
> of years with FDA, our impression is that a change of something on the
> order of 2 diopters would be viewed by FDA as clinically significant.
> So, 0.75 diopter and 2 diopters are a fair amount apart. So, we took
> that suggestion or that impression very seriously as advice and sought
> to model data based on myopia progression to see where that would take
> us.
>
> This is the slide that Dr. Gwiazda showed you. Let me just refresh
> your memory. These are the control children wearing single-vision
> glasses, from the COMET study of progressive addition lenses. These
> are the real data that have been collected to date. As. Dr. Gwiazda
> mentioned, those may be collected but these are imputed data as
> follows: In the first year the single-vision group progressed 0.6
> diopter, in the second year 0.5 diopter, in the third, 0.4 diopter.
>
> So, each of these subsequent years where we have extrapolated the
> data, we have just decreased the progression rate by 0.1 diopter. You
> can do the calculations. If the children are 9.5 when they entered the
> study on average, they would be on average, 15.5 at the end of this
> curve.
>
> Now, if we then assume a pharmaceutical agent that would have a 50
> percent treatment effect, here is what we see. So, each year the
> progression of myopia is reduced by 50 percent and out at six years
> what we find, if we were comparing the means of these two groups\--the
> first analysis method that I mentioned\--what we would see is that we
> could only see a difference between the means of the two groups of a
> diopter, not the 2 diopters that I presented before as perhaps being
> required for clinical significance. So, given the underlying
> distribution of the progression of myopia in the target population, it
> means that at most, if you started with average age 9.5 year olds, you
> would find a diopter difference between the two, not 2 diopters.
>
> In the spirit of taking that advice seriously and in the spirit of
> compromise we might propose a primary efficacy variable based on that
> comparison of proportions between the two treatment groups where the
> cut point, the clinically meaningful cut point that we would use would
> be 2 diopters or more of myopia progression. So, that would bring into
> play the 2 diopters clinically meaningful endpoint but it would be
> based on a proportions analysis.
>
> To summarize, the proposed population to study might be 6-12 year old
> children who have myopia of 1-4 diopters at the time the study begins.
>
> The primary outcome would be spherical equivalent refractive error
> measured by cycloplegic auto refraction, and specified as a change
> from baseline.
>
> The study would be 30 months long. The children would be on treatment
> for 30 months. There would also be a six-month period off drug, and
> both of those periods would address the safety, efficacy, rebound
> effect, those sorts of things.
>
> Lastly, what we have sort of proposed in light of this 0.75 diopter
> overlay is a primary efficacy variable that is based on a comparison
> of the proportions between treatment and placebo groups who progress
> at least 2 diopters in their myopia.
>
> So, that is an overview to begin your discussion. With that, I would
> like to turn it back over to Dr. Green.
>
> **Overall Summary**
>
> DR. GREEN: Thank you. Dr. Zadnik, Dr. Miller and Dr. Gwiazda, I would
> like to thank each of you for your presentations.
>
> In terms of an overall summary, the blurry vision from progressing
> myopia is important to children, to parents and to eye care
> practitioners. Dr. Miller I think very effectively presented a
> simulation of what that is like.
>
> We have proposed an indication for reduction of myopia progression in
> children diagnosed with juvenile-onset myopia. As you just heard from
> Dr. Zadnik, we recognize that for a development program there is a
> requirement to define a primary efficacy variable, and what we have
> attempted to do is to take into consideration all the feedback that we
> have gotten, but to try to do it in a way that we think would allow
> for a feasible development of a pharmacologic agent.
>
> We do, however, believe that a change in refractive error of 0.75
> diopter is a clinically significant change. We have proposed a study
> design to assess any pharmacologic treatment of juvenile-onset myopia.
>
> That concludes our presentation. On behalf of Novartis Ophthalmic, I
> would like to thank the FDA. I would like to thank the panel members
> for organizing this and allowing us to participate. Thank you for your
> attention.
>
> DR. GATES: The committee would like to thank the FDA for their
> presentation and also Novartis. We will adjourn for a 20-minute break
> and convene at 9:45.
>
> \[Brier recess\]
>
> DR. GATES: At this time we will reconvene the meeting. If you came in
> after the initial introductions, I am going to ask you to introduce
> yourselves and we will again go from my right to left.
>
> DR. PLOTT: My name is Todd Plott. I am serving on the committee as an
> industry representative, non-voting member by the way. I am a
> dermatologist and have spent all my career at various pharmaceutical
> companies developing a variety of different pharmaceutical products.
>
> DR. GORMAN: I am Richard Gorman. I am a pediatrician in private
> practice. I stand on the FDA\'s Pediatric Advisory Subcommittee and I
> represent on that committee, but not here, the American Academy of
> Pediatrics, and I chair the National American Academy of Pediatric\'s
> Committee on Drugs.
>
> DR. BULL: Good morning. I am Jonca Bull, the Director of the Office of
> Drug Evaluation V.
>
> **Committee Discussion**
>
> DR. GATES: Thank you. Now we will begin our first segment for
> discussion. With the first segment of discussion I would like to start
> by asking are there any questions for Novartis from the committee or
> the FDA. So, we will open the floor.
>
> DR. BULLIMORE: Do I need to announce my name every time I speak? A
> couple of questions for Novartis. Obviously, we are embarking on a new
> phase here, a new group of drugs and new potential indications. One of
> the things that we are being asked to assess later today is
> complications of adverse event rates. Based on experiences at home and
> abroad to date, are there any specific kind of events or complications
> that the panel should be discussing today that relate to this
> particular product, be it pirenzepine or whatever other drugs are
> under development?
>
> DR. GREEN: Dr. Bullimore, I will take that question. In terms of
> pirenzepine specifically are there specific events, as you know, we
> are working on pirenzepine. We specifically have not tailored this
> presentation about pirenzepine. Pirenzepine is one example candidate
> that we are looking at. There are other candidates that other
> companies may be looking at. So, we would prefer not to talk about
> pirenzepine specifically.
>
> We chose the one percent level. It is consistent with typical
> guidelines for chronically administered drugs, but we acknowledge that
> it is a topic open for discussion.
>
> DR. BULLIMORE: I have a second question. You threw out in the course
> of the presentations two criteria for effectiveness. One was 0.75
> diopter and the other, which you inferred came out of discussion with
> the FDA, was 2 diopters. I am looking at your progression graphs that
> you presented. Am I right in assuming that, based on the COMET
> baseline and entry criteria, in order to get a 2 diopter effect you
> pretty much have to stop myopia in its tracks in a group of 9-year
> olds followed for 6 years? Is that a correct interpretation?
>
> DR. GREEN: That is a correct interpretation.
>
> DR. GORMAN: I have three questions for Novartis. Being a pediatrician,
> I get to ask all the questions the ophthalmologists might be more
> worried to ask. The mechanism of action of this class of agents, if it
> is not your particular agent, is it a growth inhibitor? If it is a
> growth inhibitor, is it planned to be administered orally or
> systemically or topically?
>
> DR. GREEN: We have a particular agent which we are looking at which is
> a muscarinic antagonist, but we are not proposing that that is the
> only mechanism of action. We are also not proposing that the route of
> administration would only be topical. It could be oral; there could be
> other ways. I think, depending on the route of administration, those
> sorts of details would probably have to be a point of further
> discussions in terms of the details of the clinical development
> program. They might affect the level of adverse event rate. They might
> affect certain details.
>
> For us, the primary open question was just simply the endpoint, the
> primary efficacy variable, how we assess the effectiveness and sort of
> the generalities of the study design.
>
> DR. GORMAN: How did you decide, or would you be willing to share your
> decision\--you call this a treatment of myopia which is, not to mince
> words, not exactly correct; you are preventing progression. How did
> you choose to treat myopic children rather than prevent myopia by
> using this in an at risk population?
>
> DR. GREEN: I will ask Dr. Zadnik to address that.
>
> DR. ZADNIK: That has been the choice of Novartis, but we have done
> quite a bit of work actually in our studies on what child is at risk
> for the development of myopia, and what we find is the best predictor
> is their refractive error at age 8. That is what we have looked at in
> our data set.
>
> It is an interesting game to try to predict either the onset of myopia
> or the progression of myopia. For example, the prediction at age 8,
> you might argue, gosh, that is already after some children have become
> myopic. We do that with about 87 percent sensitivity and about 75
> percent specificity.
>
> Let\'s see, let\'s think about that. We would accurately treat lots of
> kids, and treat kids who didn\'t need to be treated, about 25 percent
> of those. I think I have it right. So, depending upon what the drug
> was, its safety profile and its efficacy profile, you could decide I
> suppose down the line whether that kind of prediction ability was good
> enough. It kind of depends on the nature of the drug; how expensive it
> is; how safe it is; how well it works. Would you want to put those 25
> percent of children at risk? Would you want to miss the 13 percent
> that you wouldn\'t treat? So, the prediction game is an interesting
> one, and one we have been working on in my lab.
>
> DR. GORMAN: And a third question, and I promise this will be my last
> for a while, you introduced the concept of rebound, which is a concept
> that pediatricians are very comfortable with. When you speak of
> rebound, however, do you mean that you will resume the rate of myopic
> progression that you would have predicted at the start of therapy?
> Would that be an acceptable rebound, or would you hope that
> progression that continued would be at the rate predicted at the new
> age when therapy was ceased?
>
> DR. ZADNIK: I think it would be the latter. I think you would hope
> that the eye wouldn\'t just have stopped growing or showed the
> treatment effect over the period of time and then sped up in that
> period. Let\'s say, for example, a child was on a drug from age 6 to
> age 9 and then they were off it, you would hope they would grow like a
> 9-year old\'s, not like a 6-year old\'s eye.
>
> DR. GORMAN: Thank you.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: This may be too much detail at this point, but following
> along the aspects of the details of the trial and thinking about
> whether this is going to be a safety issue and, obviously, efficacy,
> and the efficacy that you are proposing is perhaps 30 months or 36
> months after being off the drug, you know, looking at the natural
> history and how children are progressing, is that sufficient? Would
> you need to treat even longer than that and how would you address that
> issue?
>
> DR. GREEN: That is a good question. We have spent a lot of time
> thinking about it. Dr. Zadnik made reference at one point to an
> international advisory panel. We have tried to get the best people
> possible to advise us on all the different aspects of this
> development.
>
> As you heard from Dr. Gwiazda, progression essentially stops by around
> age 16. So, we would anticipate that most likely you would have to
> treat until around 16. What we have found from the discussions that we
> have had though is that an exposure of 30 months in general would be
> adequate. They would feel comfortable with that much information if
> the drug were on the market. That is how the balance of all that
> played out.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: Just a point of clarification, I am not used to dealing
> with drugs, but in order to demonstrate effectiveness you proposed a
> 30-, 36-month trial but the indications for use would exceed that
> period?
>
> DR. GREEN: That is correct. I think we understand that part of our
> responsibility would be that the patients that were part of a clinical
> study, we would continue to follow those patients. We wouldn\'t just
> stop and no longer follow those patients once we had filed for
> registration.
>
> DR. GATES: Dr. Feman?
>
> DR. FEMAN: With the information that was presented so far in terms of
> the work that I think Dr. Zadnik was presenting, you have a way of
> measuring the efficacy or one that is being given to us as a
> potential. With the data that is already available and knowing what
> the natural history is, one should be able to calculate something like
> a sample size. What size population you would have to study to detect
> this. Do you have any estimates? Have your statisticians had a chance
> to review this?
>
> DR. GREEN: The sample size is going to be a function of the method of
> analysis certainly, is it a comparison of proportions; is it a
> comparison of means. It is also going to be driven by the sample size
> necessary to detect a certain level of adverse events. What we
> anticipate is that that is probably going to be the largest driving
> factor.
>
> DR. FEMAN: So, what would the number be approximately? Are you talking
> about 1,000 children or are you talking about 5,000 children?
>
> DR. GREEN: In terms of the number of children exposed, we have a
> requirement to do two Phase III, two pivotal clinical trials. So, each
> one of those trials would probably have approximately 500 children on
> drug. That is an approximate number.
>
> DR. GATES: Dr. West?
>
> DR. WEST: To review again, the children at entry would be between 6
> and 9 years of age. Is that correct?
>
> DR. GREEN: Six and 12 is what we proposed.
>
> DR. WEST: And how will you deal with girls who may be approaching
> menarche and may be at risk for pregnancy?
>
> DR. GREEN: Certainly, we would have to monitor that with pregnancy
> testing on a regular basis.
>
> DR. WEST: And logistically, how would that be accomplished?
>
> DR. GREEN: In terms of the visit schedule, do you mean?
>
> DR. WEST: Yes.
>
> DR. GREEN: I don\'t think we have finalized a specific visit schedule,
> but probably what we would anticipate is at least quarterly visits,
> something like that. But, I mean, specific logistic details\--we know
> it is an issue; we know that it has to be monitored; we know that it
> is important. We are not ignoring that but we don\'t have a specific
> plan right now.
>
> DR. WEST: Then, my second question is more urgent to me, and that is
> the choice of spherical equivalent as the outcome, which
> mathematically is inaccurate although that is what clinicians are the
> most comfortable with. The rank and file clinicians are more
> comfortable with the spherical equivalent but as the major outcome it
> is mathematically quite flawed.
>
> DR. GREEN: Okay, but I didn\'t understand the question.
>
> DR. WEST: I would hope that data other than spherical equivalent alone
> would be reported. For instance, a child who enters with a refractive
> error of minus 2, plus 1 and comes out as a minus 2.5, plus 1 would
> have a spherical equivalent change of 0.5 diopter.
>
> DR. GREEN: Okay.
>
> DR. WEST: If the treatment caused the refractive error to change to
> minus 3, plus 3, you would have thought that that child was
> successfully treated because you had no progression of spherical
> equivalent but, in fat, that child would be far worse off than if they
> had progressed according to a normal curve. So, using spherical
> equivalent as the outcome is not potentially a good choice, although I
> understand that as a choice since many practicing ophthalmologists and
> optometrists are very comfortable with spherical equivalent.
> Mathematically it is really inaccurate, and it has been shown to be
> inaccurate in the refractive surgery literature as well.
>
> DR. GREEN: If any of our experts want to comment, I will certainly ask
> you to do that, but it is also the outcome measure that is commonly
> reported and used in most clinical studies. Most of the experts that
> we talked to, that is the recommendation that we received. Would we,
> as a company, collect the details of spherical myopia and astigmatism,
> would we have that information? We would. But right now, based on what
> we know, the primary outcome measure would be spherical equivalent
> refractive error.
>
> DR. JOSEPH MILLER: It may have been somewhat myopic for us to have
> used spherical equivalent in the sense that there are three components
> to refractive error that are statistically independent of each other.
> Astigmatism comprises two of those components. Spherical equivalent is
> the third. Of the three numbers, spherical equivalent is the number
> which is directly varying with axial length and that is why it was
> selected.
>
> However, your charge was also to consider other modalities of
> treatment which include the cornea. So, if cornea is on the table, if
> treatments are being considered which theoretically could affect
> corneal curvature or lens growth, then I agree certainly that all
> three components of refractive error\--traditionally, spherical
> equivalent was the only one that was thought of as a way of
> conveniently combining the astigmatism component with the spherical
> component of refractive error. But certainly in the last two decades
> statistics have caught up with clinicians and Vision Science now
> routinely uses a three-dimensional vector to describe and track
> refractive error, and we would certainly do our analyses on those
> bases.
>
> But if the primary endpoint is being considered a treatment for
> slowing axial elongation of the eye, my suspicion is that of the three
> components the one which will be most sensitive to those changes will
> be spherical equivalent.
>
> DR. GWIAZDA: I would like to add that in the COMET trial we enrolled
> children with similar inclusion criteria that we have presented here,
> limited amounts of astigmatism, less than a diopter, and after three
> years we found very little change in either the J0 or the J45
> components. So at least in our trial, if you start with a limited
> amount of astigmatism there is not going to be a whole lot of change
> over the course of the three years. Obviously, the action of a drug
> might be different, could affect the cornea and the J0 and J45 have to
> be carefully monitored.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I think Dr. West is thinking very broadly and raises a
> good issue. One way to deal with this but perhaps still have spherical
> equivalent as the primary outcome measure, may be myopia in the most
> myopic meridian and the least myopic meridian, and astigmatism the
> secondary measures that the sponsor be asked to contribute and present
> for analysis.
>
> DR. GATES: One question for myself, is there any dilatory effect of
> this medication on the pupil?
>
> DR. GREEN: Of the specific medication that we are studying right now
> with respect to pupil dilation? Do you consider that dilatory?
>
> DR. GATES: Yes.
>
> DR. GREEN: The particular medication that we are studying does appear
> to have a mild dilatory effect. It doesn\'t mean that every medication
> studied for slowing progression of myopia would. This particular one,
> as we have reported, does have a mild effect.
>
> DR. GATES: And, as far as the cycloplegic effect compared with
> atropine?
>
> DR. GREEN: Ours does have a mild\--much, much less.
>
> DR. GATES: Any quantitation of that?
>
> DR. GREEN: None that I can report right now.
>
> DR. GORMAN: I would like to follow-up on that question and ask it from
> the opposite direction. Do people who take this new class of agents
> that you are hopefully developing need more ophthalmologic
> intervention during treatment? Do they need different glasses, or more
> glasses, more frequent exams? This is outside the clinical study that
> you are proposing, if this goes into widespread use, would they need
> more ophthalmologic intervention during the time they were on the
> medicine?
>
> DR. ZADNIK: That is an interesting question. Certainly, if it slowed
> the progression, the child, you would hypothesize, would not need the
> spectacle or prescription changes. I am sure as the drug were begun in
> usage\--you know, when a child first went on it there would be
> appropriate follow-up visits to make sure he was tolerating it well
> and the usual things you might anticipate. But, as I think about it,
> the idea would be that if their myopia slowed in its progression, they
> would not be coming in, in August or when school starts and saying,
> \"you know, I can\'t see the blackboard again, mom. I don\'t think
> these glasses are working anymore,\" because their progression would
> have been slowed.
>
> DR. GORMAN: Let me ask that question more specifically, will there be
> an acute visual change when you use the medicine?
>
> DR. ZADNIK: I mean, I guess I would ask Dr. Green to speak to that for
> this specific medicine but, as you might imagine from a whole variety
> of things, I think it would depend on the individual agent and what it
> did to the child\'s vision initially. I hadn\'t thought about that one
> before. That is a good question.
>
> DR. GREEN: I don\'t know if that answered your question but,
> unfortunately, I can\'t add a whole lot more to that.
>
> DR. GORMAN: Well, it didn\'t answer my question but it gives me pause
> in terms of study design and in terms of if there is an acute visual
> effect of any agent when you come on and off the medicine, if I can
> draw an equivalent from adult medicine, it would be like diabetics who
> get out of control and their visual acuity changes as their lenses
> swell or shrink from the glucose in their lens. It would potentially
> make the quality of life measures and visits to healthcare more
> frequent.
>
> DR. ZADNIK: Yes, I think only if there were something that happened
> apart from the visits where you would already be seeing the child for
> tolerability of the medicine to begin with. So, only if it were a
> little bit longer-term change than that would that add a visit than
> you would otherwise have incorporated in the child\'s follow-up.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: A question for Dr. Miller. In your presentation you
> mentioned using a pharmacological agent, and what would be the
> criteria for initiating a pharmacological agent in the course of
> therapy relative to the refractive error? Would it be, for example,
> more rapid progression? What would be the criteria for using that, and
> how would that be reflected in a clinical trial?
>
> DR. JOSEPH MILLER: The story that I was telling was relating to my
> experience with parents who are asking for alternatives to treatment.
> What I was relating was the fact that the one medication that has been
> shown to be effective, I did not use it and I did not give it as an
> option because the side effects were so severe.
>
> To answer your question, however, I think the question becomes why
> would patients or their parents want to be placed on this medicine?
> Why would they ask for it if it was someone requesting this, or when
> would it be recommended by a practitioner? I believe that what would
> happen is, as in the same event that I described, the child would come
> in, having gone from normal, good distance vision, at first impairment
> of distance vision where the child comes in and receives a pair of
> glasses for a very low level of myopia. Many people stabilize and
> don\'t become more myopic. But the next time that they show up and
> request a pair of glasses, I suspect that is when the questions would
> be raised.
>
> The only thing I can really speak to in terms of study design,
> however, would be our entry criteria. We believe that children who are
> listed in the entry criteria would be the children that would be the
> most likely to benefit from such a treatment initially or at least in
> the evaluation stage.
>
> DR. PLOTT: Just as a follow-up, what would be the change in refractive
> error that would typically cause a clinician to say that there has
> been a clinically significant change and I need to provide more
> glasses or go to another agent?
>
> DR. JOSEPH MILLER: That is as precisely defined as what my favorite
> color is on a given day and I have to find a shirt to match that tie.
> But the problem is that everybody has a different threshold depending
> on how much the child is whining; how much the parents are able to
> afford a new pair of glasses. If they just bought a new pair of
> glasses oftentimes there is a reluctance to replace them. But a value
> that I frequently hear from colleagues is that 0.75 diopter, 0.5
> diopter change is significant; 0.25 diopter change is not significant
> in people\'s minds. When you get to larger values of change, the
> changes are so dramatic that it is not a question whether a new pair
> of glasses are appropriate.
>
> Many insurance companies will replace glasses if there is any change
> in the prescription. One of the criteria that I hear frequently from
> practice surgery colleagues is that a laser enhancement procedure is
> offered to a postoperative patient if they are outside of a 0.75
> diopter window. So, that 0.75 diopter among adults seems to be a
> threshold of requesting a change.
>
> But in terms of how people actually act, it is largely determined by
> how fussy they are about their vision. Some people are acutely aware
> of the slightest change. We had one patient who actually owned their
> own trial lens set when I was a fellow and would refract himself.
> There are all sorts of people out there and they all have different
> demands. Was that specific enough?
>
> DR. PLOTT: Yes.
>
> DR. JOSEPH MILLER: Thank you.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: This goes back to the adverse events and what would be
> tolerated by the patient. I guess one concern I have, without speaking
> specifically about any drugs, it is going to be hard to mask the
> patients and the examiners as to who is being treated and not treated.
> The masking may be an issue. Even if it was not masked, it would be
> important to mask the people who were obtaining the refractive errors
> in the study.
>
> DR. GREEN: We would agree. At minimum, the people obtaining refractive
> error data must be masked.
>
> DR. ZADNIK: However, that is one of the arguments for using an auto
> refractor under cycloplegic conditions. If, for example, you were
> worried that the children on treatment pupils would be a little
> bigger, if everybody were cyclopleged before they headed to see the
> auto refractor I think you could say that the refraction examiner
> would be pretty well masked, and using an objective measure that
> neither he or she nor the child could really affect in a substantive
> way. So, I think the cycloplegic part of the endpoint is key to doing
> that if there is a pupil dilation effect of an agent under study.
>
> DR. GORDONSON: I agree and you are not really prescribing this. All
> you are really looking for is a change. So, I think that paradigm
> would be good.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: This is something someone might want to make a brief
> comment about, the proposed mechanism by which these drugs affect
> myopia, cycloplegics or muscarinic, are they affecting axial length?
>
> DR. GREEN: The muscarinic antagonists appear to affect axial length,
> slow the growth of the sclera.
>
> DR. STEIDL: Do you have any idea by what mechanism?
>
> DR. GREEN: Not definitive, sorry.
>
> DR. STEIDL: I guess a second, follow-up question, perhaps if I had
> extreme myopia myself I would be more sympathetic but I understand
> that people would prefer not to have to wear glasses and that sort of
> thing but, just a very broad, wide question, would this be better than
> making glasses available with more frequent exams? In other words,
> trying to give people what they need, and I understand the argument
> about being in a hotel room and be worrying about fires, and all that,
> but I am just curious, in general, why the chronic drug use in a child
> versus just more frequent exams?
>
> DR. GREEN: I think one of the things that Dr. Miller reflected when he
> made his presentation is that people continue to look for
> alternatives. The array of alternatives obviously aren\'t
> satisfactory. Last year there were approximately 1.5 million LASIK
> procedures even if people could wear contact lenses or glasses. So, we
> find that people continue to look for alternatives. The things that
> are available, glasses, they aren\'t affecting the structural changes
> and the potential impact of the structural changes is obviously very
> long-term but they are not impacting that.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: In my clinical practice it seems as though it is the
> younger onset kids, who are going a diopter a year in terms of change,
> where the parents come in with extreme alarm and they want to know
> about trials across the country to look at this. So, I am not really
> worried about those kids that are changing 0.5 diopter a year if they
> have come in especially after age 9 or 10. I am more interested in
> capturing and looking at helping the kids that come in at the younger
> age with the faster rates of progression. So, capturing that group and
> showing a change in that higher, faster changing group would be much
> more convincing to me.
>
> DR. ZADNIK: Well, I think that resonates with the evaluation of the
> proportion of children who progress some pretty high amount over the
> three years. I mean, I think 2 diopters over 30 months would perhaps
> be the younger children and the faster progressors and that analysis
> would really, in some sense, focus on them, I think, because the hard
> part is predicting who they are going to be. You get back into that
> prediction game. It is easy for a 6-year old. In our data the only
> good predictor is age but it is not perfect. So, I think that
> comparison of proportions analysis starts to get at that.
>
> DR. MILLER: We will end up studying a lot of kids that won\'t have
> anything bad happen to them to get that information because the older
> kids will not be changing that much, but yes.
>
> DR. ZADNIK: And yet we get an estimate by including them for what any
> agent would be able to do for them as well in a trial.
>
> DR. MILLER: Right.
>
> DR. GATES: If there is a cycloplegic effect to the medication, how do
> we address that particular child\'s, in the treatment groups, near
> vision needs?
>
> DR. GREEN: It depends on the degree of the cycloplegic effect. If it
> was a very significant cycloplegic effect you would probably have to
> use bifocals.
>
> DR. ZADNIK: Or take their glasses off to read if it would be profound
> enough that they would need to do that.
>
> DR. JOSEPH MILLER: Measuring accommodation disorder is very tricky in
> young children and I think that to try to get an actual number that
> measures how well a child, and how rapidly a child, and how precisely
> a child accommodates is a difficult question. So, in terms of
> generating a protocol that could give a secondary outcome measure that
> precisely measures how much accommodation disorder is a challenge for
> us, and one that we would attempt to rise to\--I can tell you that
> many children, if you encourage them appropriately, can read very,
> very fine print even if they do have an accommodation disorder. So,
> simply asking them to read an eye chart or a near card and ask how far
> down they can go may not get to the answer that we are looking for,
> and we may need to have more robust measures of accommodation in order
> to answer your question.
>
> DR. GORDONSON: Children go to school. That is the most important thing
> in their lives. There are so many things that have to be brought
> together and they have to learn. If you penalize their accommodation
> you also affect the accommodation conversions ratio. Although they may
> do well in your office, if they spend any length of time reading it
> may affect their ability and their motivation.
>
> DR. GATES: Dr. Bullimore?
>
> DR. GWIAZDA: I just wanted to mention\--excuse me, Mark, that in the
> COMET study in children, 6-12 years of age, we did objectively measure
> accommodation using a Canon R-1 auto refractor and concomitant
> measures and were able to calculate ACA ratios. So, I do believe that
> in this age group we could obtain objective measures of accommodation
> and convergence, such that we can monitor accommodation convergence
> and ACA ratios.
>
> DR. GORDONSON: Would that exclude certain children?
>
> DR. GWIAZDA: At the outset, I mean, if we measured accommodation
> initially and they had accommodative insufficiency, that is a
> possibility.
>
> DR. BULLIMORE: I think the panel here is starting to identify some of
> the safety issues and explore the way in which we might measure them.
> Clearly, for a drug that has some fundamental anti-muscarinic
> properties, presumably specific and not broad, accommodation is a
> reasonable concern and it may be worthwhile in a group of children,
> say, 10-12 diopters of accommodation, to think about how much
> reduction in accommodation we would find alarming or significant or
> would classify as unacceptable. I mean, certainly reducing a child\'s
> amplitude of accommodation to 6 D or 8 D\--speaking to somebody who is
> in their 40s, that seems an awful lot of accommodation even if it is
> reduced by 30 percent.
>
> Likewise, with pupil size, if there are concerns there we need to
> better document that, and likewise with their visual acuity. There are
> some issues that we could certainly put some parameters on today that
> might help in the develop of a guideline document. Dr. Gwiazda
> mentioned objective measures of accommodation. I think that would be a
> reasonable thing to include in a trial and some measurement of their
> visual acuity to ensure that the child is able to function on a
> day-to-day basis without too much penalization due to the therapy.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I think it is dangerous to extrapolate what our
> accommodative needs are to that of children. They may be less tolerant
> and be willing to extend less effort. Furthermore, an accommodative
> amplitude of 6-8 diopters for somebody who is of normal size and grown
> up size may be quite sufficient. Children are smaller. They have
> shorter working distances and they may have greater accommodative
> needs than we do.
>
> The second point that I thought was important to bring up is that
> although many lay people are having refractive surgery and this seems
> to be an indication of people\'s dissatisfaction with myopia and its
> treatment, I think it is extraordinarily important that the panel, the
> public and Novartis realize that almost no eye care practitioners have
> refractive surgery done on themselves.
>
> DR. BULLIMORE: I will disagree with that. I was at a meeting this
> weekend with a very-well respected refractive surgeon who, himself,
> has done 400 procedures on ophthalmologists. Now, he might have
> exaggerated a little bit but that was what he told me and I trust him
> in that regard.
>
> DR. WEST: I think that if you asked how many of us are myopic and how
> many of us have had it done, you would find\--I think that you have a
> bias, a selection bias in that population and some swaggering but, you
> know, of all the ophthalmologists in Cincinnati only one has had it
> done. I don\'t know about the optometrists. But I think it is very
> important that myopia may not be such a bad disease, especially as one
> approaches presbyopic years, especially since 50 percent of the myopes
> have refractive errors of less than 3 diopters and, in fact, that may
> be beneficial in the workplace.
>
> DR. GORDONSON: I was president of the Long Island Ophthalmological
> Society and we have the largest geographic ophthalmological society in
> the country. We have 225 members just in one county, and I don\'t know
> of any ophthalmologist that has had refractive surgery.
>
> DR. GATES: Dr. Miller, I believe you had a question.
>
> DR. MILLER: I do feel we have to really focus on the accommodative
> effects of a new medicine very carefully. I find that in some cases I
> get a sense that the child is not performing well in school because
> although they can accommodate temporarily in my office, they can\'t
> continue that accommodation long enough in a school setting to do
> well. I will make a decision to correct hyperopia that I might not
> always correct in a child with some delays or school problems.
>
> So, it is definitely a fear of mine that we could get adequate
> accommodative numbers for a ten-minute setting in a child who is very
> motivated in the office and still have some effect on their behavior,
> and perhaps we want to get some behavioral measurements as well or
> some sort of more prolonged reading accommodative measure. I am not
> familiar with all the measures you are speaking about with the COMET
> study, but it would be important to look very carefully at those in
> applicability to a school setting.
>
> DR. GWIAZDA: I agree that that is very important. In the COMET study
> we take measurements just at one point in time using a near target and
> taking a few readings using an auto refractor that has an open field
> of view so we could put targets both at near and far and measure the
> children\'s accommodation while, at the same time, we had an attached
> motorized Risley prism so that we could measure their fore areas. That
> is at one point in time.
>
> In my laboratory we are now taking measurements of accommodation and
> convergence while children are reading. So we are getting more
> naturalistic data. This is apart from the COMET study. But you are
> absolutely right that those are extremely important data, and the
> myopia research community is very aware of that.
>
> DR. MILLER: Just to follow-up, not all refractions are alike in the
> sense that, depending on how strong a cycloplegic agent you do for
> your auto refraction, you will get less reserve for accommodation with
> your glasses if you fully cycloplege with an atropine level of
> refraction. So, it also depends on how much effect your medicine has
> and what cycloplegic agent you choose for your refraction which will
> give a little more or less reserve.
>
> If you had a very, very good functional measure, then you don\'t have
> to tease all those things out. If the kid succeeds in school you know
> your answer. But otherwise you have to dissect out so that they are
> covered for that period when they are in school.
>
> DR. GWIAZDA: Yes, I agree.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: This is another general question. If someone wants to
> comment on this from Novartis, fine; if not, it is okay. But I am just
> getting confused in a sense as I look through these questions trying
> to determine what we are trying to accomplish. I would just like your
> thoughts on this. Are we trying to make people happier or are we
> trying to avoid the pathologic side effects of myopia? You know, there
> have been a lot of comments about how the need for this drug is
> mirrored in the desire to have refractive surgery which, to me, is a
> completely different issue.
>
> DR. GREEN: One of the reasons that we specifically presented that we
> weren\'t looking for an indication based on pathologic changes is
> because they are so long-term and we think it would be very difficult
> to develop an agent if that is an endpoint. So, that is why the
> endpoint we are focusing on to assess the efficacy is the refractive
> error endpoint. Long-term, would that agent result in having a
> positive impact on those things? I don\'t think we will know until we
> have long-term exposure.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: For instance, in your entry criteria if you had children
> with some myopia and then at that second visit they were already
> starting to be off the curve by some criteria, then you would be
> looking at a group where the risks involved or the potential issues
> become more reasonable to me. Half a diopter a year if they are on the
> curve, including them in the study, if they started at age 6, well,
> yes. When you get to 3-5 diopters later on, that is a problem but you
> are going to include so many kids that I don\'t consider it a problem,
> and maybe that is my bias.
>
> So, I am wondering if in your inclusion criteria it can be weighted,
> those 500 kids that you do, towards the kids that are more likely to
> have the alarmed parent. You will get them in your study, first of
> all, but that is the group of interest to me if we can\'t study
> retinal breaks ten years later.
>
> DR. GREEN: So, that group of children who are already demonstrating a
> fairly significant rate of progression at a young age is the primary
> criterion you are talking about.
>
> DR. MILLER: That is my personal interest for the first year, but I am
> not designing.
>
> DR. STEIDL: Just a follow-up, I understand that it is hard to
> determine drug efficacy with the endpoint of decreasing retinal damage
> but, to me, nonetheless, if that is ultimately what we are after I am
> going to answer these questions differently than if we are just trying
> to give people the satisfaction of lower power lenses.
>
> DR. GREEN: Ultimately what we are after is an indication for reducing
> the progression of myopia. That is what we are after.
>
> DR. GORDONSON: I think that comes down to these children, when they
> are adults will they thank you or not, and that is something you
> can\'t get at.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: Again back to the general issue, do you have an animal
> model that shows this agent or class of agents is successful?
>
> DR. GREEN: We have animal data that shows that it has an effect on
> axial elongation.
>
> DR. GORMAN: Thank you.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: Getting back a little bit to what Dr. West was saying,
> these mild myopes\--you know, sometimes we reassure the parent by
> saying your child is a little bit worse now but the payoff is when
> they hit 40 and they don\'t need bifocals and they can function to
> read. So, we should also think about if we are adding risk, if we are
> actually taking away something that has some benefit later on if they
> are in the minus 1.75 or less group or minus 2 or less group.
>
> DR. GATES: Dr. Plott
>
> DR. PLOTT: I just wanted to respond, as an industry representative
> here on the committee, to the question about long-term benefit because
> there might be risk as well as benefit. It is just very difficult for
> us in industry to develop a product that has a very, very long-term
> endpoint because at some point you have to make a decision about does
> this work and get the product to the market, otherwise it is not an
> attractive product to develop; it is not worthwhile. Sometimes we
> focus on those earlier endpoints. It is also very important to look at
> those long-term endpoints as well because, while there may or may not
> be benefit of a product long-term, it is important to know what those
> are simply for instructions. For many of our products that we develop
> it could be a very long time before we know all the things that we
> have done, and that is part of possibly recommending Phase IV clinical
> studies after an approval. It might be that a company can continue to
> observe those patients and measure the long-term outcomes.
>
> DR. JOSEPH MILLER: Could I respond to Dr. Miller\'s question or
> comment? I wish that I reasonably foresaw a medication that was 100
> percent effective in stopping myopia in its tracks. If that were the
> case, we could make a rational decision to stop myopia at 1.5
> diopters, 1.75 diopters. You could probably get some kind of informed
> consent signed by the parent that said, \"I will guarantee not to sue
> you for stopping at 1.5 instead of 2.\" I am just projecting if this
> were a medication that was so designer in origin that you could
> specify what the myopia would end at when the person was an adult. But
> that is not the case. We are talking about a trial with entry criteria
> of a diopter of myopia, and if your personal suspicion is that your
> child would be happiest if as an adult they were minus 1.5 and they
> were 45 and could sort of struggle along without glasses either up
> close or far away, and that is the desired endpoint for your child,
> you have to know with absolute certainty that your child is the child
> that is going to stop at 1.5 either on this medicine or off this
> medicine.
>
> But with our entry criteria, many of these children that would be
> entered may stop on their own naturally at 1.5, or they may have been
> the child that would have gone on to be a minus 3 or minus 4 but, if
> on treatment, they would stop at minus 1.5. So, some of these kids
> would end up at 1.5 because of treatment, others would end up at 1.5
> in the placebo group.
>
> DR. GATES: Have there been any other trials of this medication outside
> the United States, human trials?
>
> DR. GREEN: Of our particular medication? Yes, in Asia.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: Again as a non-expert, are any of the mechanical
> procedures necessary to the outcome measures fairly variably at
> different ages? Are there lower age limits for automated refraction or
> cycloplegic refraction or ultrasonic axial measurement length? Is
> there an age at which that becomes unreliable at the younger end?
>
> DR. ZADNIK: I can answer that. Our longitudinal study has started with
> children in the first grade, average age 6, 6.5. We have done
> ultrasound contact axial length measures in those children from the
> very beginning of the study, as well as auto refraction, as well as
> the kind of detailed accommodative measures that Dr. Gwiazda described
> and even a video system where we videotape the shape of the surfaces
> of the crystalline lens while the child holds his or her eye still and
> looks at a light. In my experience, children as young as 6, the
> youngest age for these entry criteria\--the kinds of measurements you
> need to take are really pretty easy to do actually and we don\'t see a
> huge variability in the performance of those measures as a function of
> age within this range.
>
> DR. GORMAN: Do they vary between practitioners? If age is not a
> factor, would there be reproducibility if you measured child A and
> then researcher B measured child A?
>
> DR. GWIAZDA: I can answer that from the COMET study. When we designed
> our protocol we had optometrists who had never taken axial length
> measures before, and some of them wondered how variable the data might
> be, especially in the young children, the 6, 7, 8 year olds. So, we
> had training and certification. After the three years of data
> collection, we are about to publish a paper reporting that the axial
> length measurements, using slit lamp mounted probe, are remarkably
> repeatable across examiners and across children.
>
> DR. GORMAN: Thank you.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: In your study design it will be important\--I understand
> the idea of the cycloplegic auto refraction for the glasses aspect, as
> a pediatric ophthalmologist, I understand that. But it will be
> important to do a very good screening evaluation at the beginning to
> make sure you are not missing someone with a family history of
> juvenile retinoschisis, something hidden that might be seen at the
> periphery, or a clinical history with a family that might be vague,
> because that would really skew your progression of myopia. So, we will
> need to be sure that we don\'t have those hidden factors.
>
> DR. ZADNIK: I would agree. The implementation of that last entry
> criterion, no ocular, systemic, no neurological conditions that would
> develop refractive development, it would be very important to make
> sure you could find those.
>
> DR. GATES: Dr. West?
>
> DR. WEST: Knowing that a pharmaceutical in this class of drugs was
> tested in Asia where the progression of myopia is higher, how is it
> proposed or how can it be designed so that we get adequate
> representation among different racial and ethnic groups which may have
> different predispositions to progress in their myopia?
>
> DR. GREEN: In terms of the United States, ensuring that we have a
> representative sample in the United States?
>
> DR. WEST: Yes. For instance, as Dr. Miller brought out, if children
> whose myopia is progressing at a greater rate have more concerned
> parents, would there be an enrollment? I don\'t think you can have all
> white kids, all black kids or all Asian kids. Even among subgroups of
> those there may be different predispositions for refractive
> progression.
>
> DR. GREEN: I mean, there could be and I think that is one of the
> purposes of multicenter, randomized clinical studies across many, many
> centers of the United States. As you know, some studies require some
> sort of stratification. At this point we wouldn\'t propose that but we
> are certainly open to discussion.
>
> DR. GWIAZDA: I should say that in the COMET study we worked very hard
> to choose our centers in parts of the country where we would make sure
> that we had an adequate number of Hispanics and African American and
> white children. We tried to get a number of Asian children but our
> numbers fell a bit short in that ethnic group.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I don\'t know how to do this but in your randomization you
> almost want to have some sort of balancing for degree of parental
> myopia and a degree in the family history, or a cap on the number of,
> you know, minus 6 or above below age 8 in the different groups, or
> your two groups will be very different because there is no good way to
> balance for genetic loading. I don\'t know\--you are going to have
> parents wanting to participate if they have the problem.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: If I can add sort of a second part to that question,
> what really is the state of our knowledge regarding progression as a
> function of race, as a function of parental history? If you enrolled
> patients based the proposed entry criteria, is there strong evidence
> that you would see variations in progression by race and family
> history, or is it so moot that stratification is not necessary?
>
> DR. ZADNIK: I am going to tell you we have looked at the prediction of
> fast progression in our data set of 5,000 children and of all
> ethnicities, save native Americans on which we don\'t have the data
> yet, and we find the only statistically significant predictor of rapid
> progression of myopia is age of onset, not number of myopia parents,
> not race. One of the things we are finding in these different ethnic
> groups is that myopia is myopia, is myopia and, to our surprise, we
> have not even found in Asian Americans that being Asian is a predictor
> of them being a fast progressor, although that seems
> counter-intuitive. Most of the data we have about rapid progression in
> Asians is from Asia and I think much of our information to date, or
> clinical impressions are that the Asian children are in more often and
> progressing more rapidly. But in our big data set we have so far found
> the only significant predictor of rapid progression to be age of
> onset. However, in our data set we enroll everybody at age 6 and
> follow them to age 14 so we are waiting for the myopes to ripen in
> that data set so that we can learn more about them and how to predict
> both their onset and their progression.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: Every time I have a myopic child in the chair, I always
> turn to the mother\--usually the mother, and if she is not wearing
> glasses I ask her if she is wearing contact lenses and I am surprised
> how often she says, oh, this is not my child; this is an adopted
> child. So, I think maternity can be in question and certainly it is a
> wise man who knows his father\--
>
> \[Laughter\]
>
> \--so it is very hard to know exactly what you are dealing with, and
> the only thing to do this is with a DNA study and I think that the
> whole area is a bag of worms and you shouldn\'t go there.
>
> DR. BULLIMORE: So, what I am hearing, if we were in the process of
> putting down some guidance here, is if there is no compelling reason
> to stratify based on parental history and race, then it shouldn\'t be
> a requirement or, you know, we could place the burden on the sponsor
> to justify whatever strategy they chose to pursue.
>
> Since I have the microphone on, I have a question for Dr. Gorman. We
> have talked about loss of accommodation, school achievement and
> difficulties. Are there any standardized tests that you are aware of
> that would be appropriate to include in a protocol as a measure of
> safety to make sure that the children aren\'t being impaired by the
> use of the drug? Maybe that is something we can come back to later.
>
> DR. GORMAN: There is an analog classroom that is used repetitively in
> ADD work where children are put in a classroom situation for an 8-12
> hour period, which even by my children\'s school day is long. Then
> they are observed for their performance during the course of those 12
> hours by trained observers every 15 minutes. They are looking at
> activity levels but I am sure it would not take a large modification
> to see if they were able to perform for accommodative issues over
> those particular periods of time. So, there is a model out there. I am
> not aware if it has ever been used for visual issues.
>
> DR. BULLIMORE: I think you probably made the sponsor very nervous with
> that 8-12 hour requirement, but I think it is something we should
> discuss further in terms of ensuring that any drug that is being
> evaluated is safe.
>
> DR. GORMAN: Having only been cyclopleged twice in my career, that 8-12
> hours will come as no surprise to them because they will have other
> difficulties when they cycloplege them at the beginning. I also think
> that the report card is an excellent measure of school performance.
>
> DR. GATES: Any other comments pertaining to this line of questioning?
>
> DR. MILLER: Related, not exactly the same. If we had some data on this
> particular medication in terms of how long there is a cycloplegic
> effect in a child and the degree, some quantification, then we might
> not ask so many questions about this. But it would be nice to know
> just a little bit more in a subset of kids in helping the design
> because it is very cumbersome to do this testing, checking
> accommodative function for days on end. I mean, we have to be
> practical because these are healthy kids. So, it would be interesting
> to know more about that when it is available, or to suggest perhaps a
> subset, a small subset of information on that to help with the design
> of the full trial.
>
> DR. GREEN: Just considering generalities, is it possible to consider
> with respect to in general what effect on accommodative reserve would
> heighten more concern in terms of thinking about a general guidance?
> There is this particular medication but there are other medications
> that may or may not have any effect at all, or may have more effect or
> less effect.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Maybe I misunderstood you but my understanding is that
> there is no real good hypothesis as to how this medication affects
> myopia. So, number one, I am concerned about its implications in the
> eye but also for systemic involvement since drops go beyond the eye.
> Did you say that you have a dog model? Did I understand that?
>
> DR. GREEN: I didn\'t say a dog model. We have a preclinical model.
>
> DR. STEIDL: Preclinical? I am just curious if you have any information
> on any of these medicines as to structurally what is happening, as to
> size or interweaving of collagen changing. Is it altering structurally
> the tissue from what you would typically find in myopia? Do you have
> any information on that?
>
> DR. GREEN: For our particular medication, nothing that I could present
> right now but, certainly, those type of things would be things that we
> would have to present to talk about for a specific example.
>
> DR. STEIDL: Because depending upon its mechanism in a growing child,
> it could have implications that are concerning.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: You mentioned that for these patients their mean
> progression is 0.5 diopters per year, and criteria have been proposed
> for a 2 diopter change. That would imply that you would need to follow
> the average patient for four years, which would be a pretty formidable
> study and a lot of drug exposure before you had any results. What is
> the rationale for that level of change, that mean level of change of 2
> diopters?
>
> DR. GREEN: In terms of a comparison of proportions?
>
> DR. PLOTT: For a primary efficacy variable because, you know, that
> level really is going to drive the design of your trial, and as a mean
> change either your trial is too short or 2 diopters is a huge change
> to try to capture there. Looking at it as a proportion of patients is
> an interesting idea. In dermatology we do that but with a PASI score
> of 75, the number of people that reach that kind of clearance. But I
> wonder if you would just address the rationale for that level.
>
> DR. GREEN: Sure. The rationale for that level of change was driven to
> a large extent by a lot of the discussions that we had, our
> impressions from a lot of the discussions that we have had with the
> agency. In looking at the data that we have, our own data, and sort of
> projecting what would be feasible, what we thought might be
> achievable, that is where that arose from.
>
> DR. PLOTT: The 2 diopters is achievable? Is that what you are saying?
>
> DR. GREEN: We believe that it would be achievable in that period of
> time in terms of a comparison of proportions showing a statistically
> significant difference.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I am confused. You are saying that a 2 diopter
> reduction is achievable in terms of a comparison of means?
>
> DR. GREEN: No, not in terms of a comparison of means, in terms of
> comparing the proportion of patients that progress by 2 diopters or
> greater. That comparison over a 30-month period we think is
> achievable. We do not think that that level of threshold is necessary.
> We think that it goes beyond the level of clinical significance. As we
> have made the argument, we think a change of 0.75 diopter in
> refractive error is a clinically significant change and that is the
> hurdle that we would ideally propose to use whether it is a comparison
> of means or even if it was a comparison of proportions. Even if we had
> a primary variable based on a comparison of proportions of 2 diopters,
> we would still look at many of the cuts in the data. But we have to
> define a primary variable.
>
> DR. BULLIMORE: So, the 2 diopters came from the agency?
>
> DR. ZADNIK: Yes.
>
> DR. BULLIMORE: Was it presented with the same level of justification
> that you made for the 0.75 criteria or was it just a sort of arbitrary
> number that somebody pulled out of thin air?
>
> DR. GREEN: It was the result of a lot of discussions.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: Well, it would seem to me that this is going to be a very
> big treatment effect here that you are talking about and we may need a
> longer trial to get that sort of effect, I would think.
>
> DR. GREEN: We are not claiming that the proportion progressing by 2
> diopters or greater in this data set over a 30-month period would be a
> huge amount, but from the data that we have, when we look at the
> numbers that could progress and we think about potential treatment
> effect, if we were forced to use this hurdle, we could show a
> statistically significant difference. Again, our preference would be
> to use a hurdle of 0.75 diopters. We think that is a clinically
> significant hurdle.
>
> DR. CHEW: Well, judging from the COMET trial, unless you have a larger
> treatment effect you are going to need much larger numbers or a longer
> trial, and perhaps you may even need a three-arm trial. You are
> proposing to stop it at 30 months for one group. You may need longer
> treatment for some of these others to see that.
>
> DR. GREEN: But the COMET data you are looking at is the difference of
> means.
>
> DR. CHEW: Sure.
>
> DR. GREEN: So, we haven\'t seen that data broken down dichotomously.
>
> DR. CHEW: Sure.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: Perhaps a different strategy would be to study just the
> younger age group, the ones that are really the ones you want to catch
> early because they are going to hit the bigger numbers so to test 500
> of the 6-9 year olds or 6-10 year olds you have a higher proportion of
> the hit rate of the ones that are going to have the rapid progression.
> Or, perhaps we could reconsider a lower target or if we were looking
> more at the ones that will become pathologic based on some more of
> your data.
>
> DR. ZADNIK: Yes, you could certainly manipulate the orange curve I
> showed by changing the entry criteria. Right? I mean, younger; if
> Asian bore out to be true; girls as opposed to boys. There are ways
> you could manipulate that to change that COMET curve that I showed in
> terms of patients. What you would have to consider is where you would
> end up in terms of would you have an indication then that was only for
> this drug in 6-year old Asian girls who happen to be 1.75 diopters.
>
> DR. MILLER: And that gets back to my own interest in the more
> pathologic group. But if you are going to say you are going to apply
> it to the ones that end up ultimately with very mild myopia, then
> perhaps 2 diopters proportion is a reasonable number.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: To pick up on something I heard earlier, it seems that
> your sample size of 500 is going to be driven by the adverse event
> rates rather than the progression rates. It seems to me that with that
> many subjects you are going to be able to answer both Dr. Miller\'s
> questions and assess it in a more generalizable population quite
> comfortably. Obviously, the panel, the public, the community is going
> to take great interest in not only the primary outcomes but also the
> subgroup analyses to see which groups benefit most. Intuitively, one
> would expect your hypothesis to be borne out by the data.
>
> The other thing I want to put on the table is that all of us, as
> clinicians, have been confronted by the parent of the myopic child who
> asks us, you know, what can be done to slow the progression but, in
> light of what has been said about family history we have probably also
> been confronted by a pair of myopic breeders who are worried about
> their offspring and saying, you know, what can be done to prevent it.
>
> I don\'t want to be making strategic or business decisions for the
> sponsor or anybody else, but how does the panel feel about trials of
> drugs, of any drugs, on pre-myopic individuals, high risk individuals?
> If you look at the data, if you have two myopic parents and if you
> throw in a myopic sibling as well you probably have a high risk of
> that child becoming myopic. How would we feel about administering a
> drug to a as yet non-myopic kid to see whether the myopia could be
> prevented or, when it develops, to modulate its severity?
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: Having dealt with this issue in pediatric drug development
> for a lot of years, it wouldn\'t be the group you would choose first,
> but, not speaking for the sponsor but trying to think like a sponsor,
> if it is effective in preventing the progression of myopia and if it
> has a very lovely side effect or adverse event profile the temptation
> to use it by practitioners in groups that are not myopic but at high
> risk would be irresistible.
>
> DR. BULLIMORE: Do you see with other drugs a drug being developed for
> a group of children with a given condition and then it being used on
> an off-label basis on other children?
>
> DR. GORMAN: I can use good examples of that and bad examples. I can
> start with Acutane, a drug developed for nodular cystic acne under
> basically an orphan indication, projected to be used in less than
> 50,000 children. I think it had six million new prescriptions written
> last year. So, acne being an issue of adolescence, it was designed for
> severe acne; it is incredibly effective but it was rapidly generalized
> for all acne. So, there was a case of a drug that was designed for a
> very specific indication and was rapidly generalized.
>
> For the group of parents who wish their children never to wear
> glasses, if this drug turns out to be safe and effective to prevent
> progression, I think it would be irresistible for them not to try it.
> They would try it.
>
> DR. BULLIMORE: And from a regulatory point of view, how palatable is
> that to the agency?
>
> DR. CHAMBERS: The agency believes that if there is a high likelihood
> that a product would be used in that particular indication, we
> generally believe it should be studied prior to approving it.
>
> DR. GATES: Dr. West?
>
> DR. WEST: Can somebody go back to telling me how the period of six
> months off drug was chosen to assess potential for progression or how
> was that window chosen, and what is the scientific basis for six
> months versus three months versus a year or two years?
>
> DR. GREEN: I can\'t give you honestly a strong scientific basis. It
> was really the result of discussions among a lot of people. If you
> look at other drugs and other therapies where you might have seen some
> sort of rebound phenomenon, how quickly does it occur? You cease drug
> therapy; you have an up-regulation of a receptor, how quickly does
> that phenomenon usually happen? That is where that time frame came
> from.
>
> Does that address longer-term, over years what might happen? It
> obviously doesn\'t. That is where we recognize that we will have to
> commit to follow people long-term after the registration of the drug.
> How would that follow-up affect this particular group of off-drug
> people once the drug is approved, if they want to go back on the drug?
> Those sort of logistic details we would have to think about.
>
> DR. WEST: The problem is if a drug were proven to benefit the
> progression of myopia but the study were not powered to detect if
> people changed over to what their natural history was going to be, you
> would have people going on a medicine for no end purpose. So, I think
> it is very important that at the end you know not only what happens
> while they are on the drug, but what happens when they are off the
> drug because then you have all the expense and headache of doing a
> medicine which has an effect while you are on it but nothing really at
> the end, anyway.
>
> DR. GREEN: Yes, I certainly understand your point, but I guess for the
> development of lots of chronically administered drugs where
> potentially people are going to go off or change to some different
> type of therapy with a different pharmacologic action\--I guess that
> potential is there and I don\'t know that that requirement of
> understanding the incidence of that rebound effect that might or might
> not happen is typically required.
>
> DR. WEST: But as a parent, giving a medicine potentially twice a day
> for three years, and the headache of doing that and the expense, the
> cost to the insurers and parents, is going to be large and if it works
> while I am on it but in the end it doesn\'t make any difference
> anyway, what is the use of the three years of treating? I think it is
> very important what happens at the end.
>
> DR. GREEN: I think it is important to know what happens and I think
> that is the basis for the commitment to follow people for that
> extended period of time. I guess, you know, it is always hard to
> project what sample of people you would have. People drop out; people
> move; people\'s lives change. You run a clinical study and you do the
> best you can. You have some number at that point. Would that be
> reflective of answering the question that you are asking? We think
> that it would be because it is difficult to project all of those
> different variables. We think it would be reflective; it would be
> indicative of what you could expect.
>
> DR. WEST: But you have just told me that you really don\'t have any
> modeling or that you don\'t have any way to predict, to know that six
> months will be sufficient power-wise, sample size-wise. This is a
> medication that has such huge potential for use both on-label and
> off-label afterwards that it is a huge cost to society and I think it
> really behooves a potential sponsor to know what is going to happen
> after the medication. If the indication is only to retard or stop the
> progression of myopia, which is something that people would like but,
> as Dr. Steidl said, really where is the true morbidity medically? It
> is in the complications of the myopia later, not of the refractive
> error.
>
> DR. GREEN: Maybe I don\'t understand. Are you recommending a sample
> size in which at later ages we would be able to pick up differences in
> retinal complications?
>
> DR. WEST: No, no, no. I think everybody here has agreed that the issue
> of the complications, the medical complications of the myopia, meaning
> potentially retinal complications, glaucoma, cataract, that it is
> probably not feasible to study those. But I am trying to understand
> why it is not feasible to know what the rate of recidivism is for the
> myopia after the drug is discontinued. Because if there is significant
> recidivism, then it negates the benefit of using the medication, which
> was to retard the progression. So, I am just trying to make sure that
> the study is constructed in such a way and powered in such a way that
> you would be able to tell what the recidivism is.
>
> DR. GREEN: Meaning both the short-term, let\'s say within that
> six-month window, and then the long-term at the age of 16?
>
> DR. WEST: Yes.
>
> DR. GREEN: You are trying to address both?
>
> DR. WEST: If, once you stop the medication you go back to what you
> were going to be anyway, then the long-term benefit of not being
> myopic is far smaller. Then you only have the school age benefit of
> not wearing glasses.
>
> DR. GREEN: In terms of the short-term benefit, let\'s say a six-month
> period off drug, I think most likely the sample size we are talking
> about and the retention of patients would answer that question. In
> terms of the long-term, at the age of 16, I think that is something
> that requires some additional discussion.
>
> DR. GATES: Any other comments along the line of this?
>
> DR. CHEW: I would agree with Dr. West. I think it is very important to
> really look at what happens. Six months if really too short for, you
> know, a long period for quite a cost and perhaps you may need as long
> as two years to check that out, and perhaps have another arm in which
> you are extending the treatment even further. Because what I heard
> earlier was that you are going to treat them for 30 months and, if it
> works maybe they will do it off-label for a longer period of time. So,
> why not study it now and see what happens with longer term. So, what I
> am suggesting is I think your follow-up needs to be longer than six
> months. I think you need to have a longer period of time to see what
> happens with those patients as time goes on.
>
> DR. GREEN: I think one of our questions though is the amount of
> follow-up that we would and should commit to as a sponsor to
> understand that long term.
>
> DR. GATES: Other comments on this line? Dr. Miller?
>
> DR. MILLER: Isn\'t this somewhat of a statistical question? If we know
> the curve change per year, when would you suddenly be alarmed that
> there was a recurrence? At what time period? If you saw twice as much
> as the average curve? To what time point statistically do you have to
> follow them to answer this question? Six months sounds a little short
> to me if the mean is 0.5 diopter a year and there are errors in our
> measurement, which might be 0.25 diopter or 0.5 diopter right there.
> So, there must be a statistical way to say this is the statistical
> answer and then we can make a clinical judgment too.
>
> Clinically, my best answer would be, you know, where are they at age
> 16? That is the ultimate gold standard answer but that is not
> practical. If you do include the older age kids in your study, then
> you will have a group that stops and you will know they should have
> got to their historical endpoint. So, that is an advantage of
> including the older age group.
>
> Do you see what I am saying? Is there a statistical answer and then
> what is the reasonable clinical answer that we can come to?
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Along those lines, it seems like the real question is what
> is the rate after cessation of the drug? Is it zero? In other words,
> have you fixed the myopia? Does it continue at the previous rate? Or,
> does it accelerate to the point to where the effect is lost? I have to
> agree with Dr. Chew that my gut feeling is that you need a couple of
> years to do that, and then you would probably want a small group to
> follow for long-term effects, ideally. I don\'t see how you could do
> that in six months.
>
> DR. GREEN: I would agree. The question is what amount of that
> follow-up would be adequate to support an application to register the
> drug. That doesn\'t mean that that would be the end of the follow-up
> period. It doesn\'t mean that would be the end of the observation
> period.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I have a question for the agency on this. Recently a
> precedent\--maybe it is not a precedent but it was a precedent to
> me\--was set with a drug, IRESSA, that was approved while it was still
> in clinical trials for an agent for cancer that was shown to have some
> effectiveness but still hadn\'t been studied for side
> effects\--partial approval; accelerated approval. Is that now a
> recognized class of approvals in the FDA or was that a once in a
> lifetime event?
>
> DR. BULL: I think that setting, particularly when you get into
> diseases where the outcome is basically death, cancer therapies, is in
> a class by itself. In terms of citing the example of IRESSA, that is
> not a broad standard. It is a standard that is very specific to
> specific settings where you are basically looking at outcomes that are
> attached to mortality rather than the kinds of settings that we are
> discussing here today. That is not a broadly applied standard. That is
> something that really is on a case-by-case basis and specific to a
> specific type of setting for the kind of disease that the drug is
> attempting to impact.
>
> DR. GORMAN: Under the 1998 Pediatric Rule, which has now been
> suspended, you would have a regulatory mechanism to require
> pharmaceutical companies to conduct trials after approval. Is there
> any mechanism in place today that requires studies after approval?
>
> DR. BULL: Those are generally called Phase IV commitments and those
> can be conditions of approval. Certainly, in instances, say, in a
> setting such as IRESSA where basically a surrogate is used and then
> you try to attach that to a longer-term outcome but there is a
> credible case made that the drug demonstrates sufficient benefit that
> you can attach to a more clinically meaningful outcome at a later time
> based on further study of the drug. that is a mechanism.
>
> I think what you are saying here in terms of this particular setting,
> and whether or not there are long-term outcomes that one would look at
> post-approval, those are certainly areas that could be part of the
> conditions of approval for a specific product even in this setting.
>
> DR. GORMAN: One of the impetuses for the 1998 Pediatric Rule was the
> fact that less than 20 percent of Phase IV commitments for pediatric
> studies were ever implemented and no adult indication was ever pulled
> for the lack of those studies. Has there ever been a case where a
> Phase IV commitment has not been met and a drug has been approved for
> an adult indication?
>
> DR. CHAMBERS: We are currently not aware of any that you are talking
> about. But if I come back to the area of ophthalmology, that your
> percentage that you are talking about is not true. In fact, virtually
> all of the Phase IV requirements were tracked and were followed and
> were carried out. We are not anticipating that that would be an issue.
>
> DR. BULL: I would also add that for historical data that you cited the
> agency is definitely undertaking a much more vigilant process for
> tracking Phase IV commitments, and we don\'t see having these
> commitments in an approval and not following through on it. We are
> definitely being much more vigilant in that regard.
>
> DR. GORMAN: If I sounded harsh, it is because I am particularly prone
> to hearing those commitments for pediatric studies that were not
> followed through on. I guess the question still remains if a Phase IV
> commitment was not met, have you ever pulled approval for a drug after
> they committed for a Phase IV study and then did not provide it?
>
> DR. BULL: I am not familiar with any. We could certainly look into
> that and get back to you.
>
> DR. GORMAN: Thank you.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: Just to agree with Dr. West and some of the other folks
> who have been talking about this, I think six months even in a
> pre-approval process may be a little too short. I would like to see
> something closer to a year of washout to see if there is any profound
> rebound.
>
> But what I am hearing also from the comments from the agency and from
> the panel is that it is reasonable to expect that six months or a year
> be available when the drug was considered for approval. There seems to
> be a clear commitment on the part of this sponsor and an interest from
> the panel to follow those patients in Phase IV. Is that the same as
> post-market surveillance? That seems to be where we are heading on
> this particular issue.
>
> DR. GATES: Dr. Chambers?
>
> DR. CHAMBERS: Post-market surveillance and Phase IV are not the same
> on the drug side. Phase IV would be specific commitments that would be
> attached to the approval letter and would be outlined and would be
> expected to be completed. Post-marketing is something that continues
> virtually indefinitely following the approval of the drug.
>
> DR. BULLIMORE: Then strike everything I said about post-market and
> replace it with Phase IV, please.
>
> DR. GATES: Dr. West?
>
> DR. WEST: Regarding the follow-up, I am not necessarily saying that I
> think six months is too short. I don\'t think that we mathematically
> and model-wise know what the right answer is and I think it is foolish
> to say that six months is the right length or one year is the right
> length. What I am looking for from the sponsor is that they will be
> able to demonstrate to me that the follow-up time is sufficient to
> demonstrate a sustained benefit from treatment which will be given to
> children. Children will be asked to participate as subjects, and I
> think we owe it to the potential beneficiaries of treatment and
> certainly the subjects and their families who would participate that
> the treatment benefit for this disorder is sustained, not just that it
> works but, more importantly, that the effect is sustained. I am
> looking for somebody to tell me how long can we reasonably think that
> we could do this. I am not asking to follow children to their grave,
> just for a mathematically long enough period to have a reasonably
> degree of certainty that the treatment benefit would be sustained and
> of such a magnitude that it would be clinically important.
>
> DR. GREEN: Your question though seems to be\--maybe what I am not
> understanding is do you want this answer prior to an application for
> registration? Or, do you ultimately want this answer at the age of 16
> when, presumably, myopia progression stops? Or, if we have an
> understanding of a mean rate of progression over a year and we have a
> cohort that we have taken off for a year and we look at what their
> progression is so we can make some statements about the continued
> benefit of the drug? What specific issue is your concern?
>
> DR. WEST: I would imagine since there were overseas trials of this
> medication in human subjects that there has been\--I would hope there
> has been some follow-up of that cohort and that you would know, now
> that they are off drug, what a range of recurrence or non-recurrence
> was, and that you could take that time course of recurrence or
> stability and match that against what the typical progression would be
> over a period of time for that age group of children and that we would
> have sufficient follow-up. I am not saying that it needs to be a
> certain length but that it would be of sufficient time that,
> certainly, you could statistically draw conclusions about whether
> there was recurrence of the myopia; whether you get back to your old
> curve or stay on a good curve. What is the hope? Because you are
> asking patients to commit for a long time to treatment eventually with
> a medication like this.
>
> DR. GATES: Are there any more questions or comments for Novartis?
>
> DR. FEMAN: I was just wondering if somebody could repeat\--I think we
> mentioned it earlier but I forget who was the one that raised the
> question, the drug that they are looking at now as a proposal or as a
> concept is being done in what manner? It is used as a drop once a day?
> Twice a day? Once a week? Once a month? How is this done?
>
> DR. GREEN: The particular compound that we are looking at right now is
> a gel that is applied twice a day.
>
> DR. FEMAN: And when this gel is applied, what does it do to vision at
> the moment it is applied? It blurs the vision obviously because it is
> a gel, at the minute that you put it in. How long does the gel itself
> blur the vision? Are we saying you are taking a 6-year old and you are
> going to blur the vision for two hours after you put it in, and blur
> it again in the evening? At breakfast time before they go to school,
> if they go to school, and again at lunchtime or again in the evening
> so they can\'t watch television? Again, just with this hypothetical
> drug because this may not be the one that you want to study, but tell
> us about the mechanism of what you are doing here.
>
> DR. GREEN: Well, I think it is hard to answer the mechanism of what we
> are doing because right now I am not in a position to talk about the
> details of if there is a mild cycloplegic effect how long it may
> affect vision, which probably is very, very minimal. But there could
> be other drugs that have other side effects separate from vision that
> would have to be considered and would have to be part of the plan. I
> don\'t think that adequately answers your question but I am trying not
> to specifically talk about this one drug because it is just this one
> drug.
>
> **Committee Discussion of Questions from the FDA**
>
> DR. GATES: Any other comments? Once we start with our discussion of
> the questions we won\'t be able to go back and ask any more questions
> of the company. If not, why don\'t we start with an open discussion of
> question number one in your handout?
>
> Excuse me, there is a correction. We are going to have the open public
> hearing now. Does anybody have a comment from the gallery?
>
> \[No response\]
>
> It appears no one has a comment so now we can start off with our
> questions and this discussion is confined to the committee. Let\'s
> start with an open discussion of question one. We will come back later
> and vote after lunch. We can have more time for discussion at that
> time. We may all disagree; we may have a consensus but this will be a
> time where we will just go around and discuss what we think about each
> individual question. We will start off on my left, if you would. Dr.
> Plott, if you would begin?
>
> DR. PLOTT: Ms. Topper, am I allowed to participate in this part?
>
> MS. TOPPER: Because you are industry rep, you are allowed to
> participate in discussion but when we take a vote you may not
> participate in the vote.
>
> DR. PLOTT: Thank you for that clarification. I think it is important
> for this question to answer it relative to the way that the protocol
> would be designed because that is our task today. I think it is
> important for this particular agent that the patient population be
> characterized as being one of a certain type, whether it be
> progressive or stable. But if the indication that is being sought is
> for a progressive indication, I think the population has to be
> reflected. You, know, what is the minimum rate? I think that is
> something that just has to be defined in the protocol and probably be
> better answered by other experts.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I think the question about minimum rate over amount and time
> of refractive change really depends upon the accuracy and reliability
> of the measures that are being used to assess it. So, if the tool has
> very good reliability, has small error, then one can detect a small
> change. So, I don\'t know that it is possible to be able to answer
> that question without knowing what the measure is.
>
> DR. GATES: Dr. Chambers?
>
> DR. CHAMBERS: For the purposes of this question what we were thinking
> of defining is basically in diopters. How much of a change in diopters
> would you consider someone as not changing or as progressing? For
> example, 0.5 diopter over a year, would you consider that as being
> stable, or if somebody didn\'t change within 0.25 diopter over six
> months? How would you know somebody was changing versus not changing
> in terms of diopters?
>
> DR. WEST: Do you mean if I know they are changing or if I consider it
> significant? For instance, if the way to assess the refractive error
> of the eye is only accurate to within 0.25 diopter, then I am not
> going to feel comfortable saying that something is progressive until
> it is 0.75 diopter. So, it really depends upon how accurate the
> measure is. I mean, if I can only measure it to within a 0.25 diopter
> or 0.5 diopter, then you couldn\'t statistically say that it was
> progressive unless it was a larger amount. I am not meaning to be
> evasive.
>
> DR. CHAMBERS: I think as we start talking about auto refractors, in
> some cases you get numbers that are in tenths of a diopter. The
> question is whether you, as a clinician, necessarily believe that
> there is a difference. Just because the auto refractor told you it was
> 0.1 and at the next visit it was 0.2, do you necessarily believe that
> that is the same or whether that is a difference? What we are
> literally looking for is when do you think somebody is staying the
> same? How much error do you think there is around somebody who is
> staying the same versus how much there is\--
>
> DR. BULLIMORE: We are talking about an individual patient\--
>
> DR. CHAMBERS: We are talking about an individual, correct.
>
> DR. BULLIMORE: \--rather than a group.
>
> DR. CHAMBERS: Correct. The group can be done mathematically; it is the
> individual.
>
> DR. BULLIMORE: For a point of information and at the risk of upsetting
> people sitting in the back over there, from the Office of Device
> Evaluation, it is kind of ironic that in a lot of the refractive
> surgery labeling myopia is defined as less than or equal to 0.5
> diopter per year as being stable from the point of view of being
> eligible to have LASIK or a similar refractive procedure. In fact, I
> have seen more recently labeling that defines stable myopia as up to a
> diopter of change.
>
> So, with that in mind, I think I would agree with Dr. West. If you
> have extreme confidence in your method of measurement, and certainly
> we have evaluated auto refractors where not only the standard
> deviation but the 95 percent limits of agreement are on the order of
> 0.25 diopter, then you could say, well, 0.5 diopter is progressing or
> anything beyond a statistically obtained confidence interval, or we
> should probably call it limits of agreement\--anything beyond that you
> would call progressing and the other side regressing.
>
> So, I think it does depend on how you measure it. If you are talking
> about subjective refraction, that is going to be more variable. As
> clinicians we might not like to admit that but it is more variable
> than cyclopleged auto refraction. It may not be any less valid. In
> fact, it may be more valid from the point of view of prescribing
> spectacles but, certainly, one would have difficulty saying that 0.25
> diopter represents a progressor on any method, and probably 0.5
> diopter would be a line in the sand. It would be my line in the sand.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: I was thinking about it and if a child came to me at 8
> and was a minus 2 myope, and came back to me when he was 10 and he was
> still a minus 2 myope, I would say stable. If he comes back to me with
> 0.5 diopter increase in myopia he is progressing. Question (c) is
> interesting. Do myopia children regress or is it just a mistake in
> your refractive day? I think some do very, very rarely but only at the
> lower levels, low ones, minus 0.75, and that is my answer.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I would agree that it is difficult, depending on how you are
> going to obtain that. I am used to doing clinical trials and doing
> subjective refractions. In fact, we had a trial where we found one
> clinic had no change in refraction for the whole, entire follow-up of
> the last three years of study \--
>
> \[Laughter\]
>
> \--and we got worried because that just didn\'t seem right. When we
> looked at the rest of our clinic, we varied between 0.5 diopter to
> 0.75 diopter for our patients at each visit. So, that is how much we
> are talking about, just measurement error with a subjective
> refraction. So, I think it is very hard to pin down exactly what you
> mean by stable and progressive. I have the disadvantage of not seeing
> children; I see adults, and adults with problems that often wax and
> wane. So, for me, a diopter is not much of a change so it depends
> where you are coming from and what you are measuring with. Perhaps
> there are machines like auto refractors that are fairly precise so
> that you may be able to get a better measurement in that sense, but
> that can be all over the map. Do you want me to say a specific number?
>
> DR. CHAMBERS: Before you go too far down the line, we are looking for
> both amount and time. The issue is how often to bring people back. So,
> if you are going to say, you know, if it doesn\'t change over a
> diopter in a week versus a diopter in a year, those are very different
> types of things.
>
> DR. CHEW: Sure. I would say 0.5 diopter in a year, to me, would be a
> change.
>
> DR. BULLIMORE: Is this from the point of view of an outcome measure or
> eligibility criteria or both?
>
> DR. CHAMBERS: We are assuming we are going to try and be consistent.
> So, if it is stable in eligibility criteria, later on in follow-up, if
> we are going to say this person has now reached this plateau and is
> stable, we will use that same criteria.
>
> DR. WEST: This is sort of an unfair question. I think the question you
> really want to get at is how clinically meaningful is a change. That
> is what you really want, isn\'t it? How meaningful is a change over
> time? That is what you really want for a trial.
>
> DR. CHAMBERS: I guess the reason I think it is not an unfair question
> is because it is a question we get asked all the time. People will try
> to put in the label, you know, we have decreased how much they are
> changing and they are now stable at this particular point of time, and
> we need definitions for those. So, these terms get used a lot and we
> would like to have relatively common use of those terms at least for
> the clinical trials. So, we are asking for help in defining these
> terms at least for the purposes of clinical trials.
>
> DR. BULLIMORE: But stable is one of those things that is very
> difficult to define. I mean, somebody once told me that a normal
> patient is just one that hasn\'t been tested enough\--
>
> \[Laughter\]
>
> \--and a stable patient may be one that you haven\'t measured enough
> times, or you haven\'t measured with sophisticated enough equipment.
> We have looked at some very nice data from Dr. Gwiazda that shows, you
> know, following what looks like a half-life curve, things are slowing
> down. When does it stop progressing? I don\'t know. I mean, we have
> people progressing into their late teens. Have you established in that
> patient that they are stable? I think 0.5 diopter per year is
> reasonable but what if you then have data at two years and they have
> progressed by 0.5 at years years? Are they progressing or are they
> stable? We have a National Institute-funded study of adult progression
> and our criteria for progression is 0.75 diopter over five years. So,
> it is a difficult one.
>
> DR. GATES: Dr. Feman?
>
> DR. FEMAN: I agree with all that has been discussed so far, but
> looking in terms of what this study might be, I think it is going to
> be balanced out to some degree since there will be some people on
> placebo and some people on drug and they are going to have masked
> examiners. So, I think 0.5 diopter per year is something that should
> be a feasible goal for them to work for in terms of whether or not
> something is progressive. By using the same type of information where
> we are going to have some on placebo and some not and having masked
> examiners, stable would be less than 0.5 diopter a year and regressing
> would be, I guess, no change at all. I guess it is someone who was
> myopic and was no longer myopic. Does that mean they become less
> myopic at 0.5 diopter a year? In spite of what Dr. Gordonson
> described, I don\'t think I have seen very many people doing that.
>
> DR. GATES: I am also leading myself toward progressive being 0.5
> diopter a year. It seems to be something we commonly see in the
> literature, with stable from zero to less than 0.25.
>
> DR. GORMAN: Sometimes it is good to be the simple country
> pediatrician. For me, I have heard both in this room and when I talk
> to my ophthalmologic friends that they prescribe new glasses at 0.5
> diopter and the patients say, \"God, that\'s better.\" So, that is
> progression because if you put a new pair of glasses on them and they
> say that is better, that is a progression that you have then
> corrected. So, if 0.5 diopter is the number where you get new glasses
> and it makes a difference, then 0.5 diopter is progression. Stable
> would be no new glasses. I guess that would vary from clinician to
> clinician whether it is 0.25 diopter or 0.5 diopter but it seems that
> 0.5 diopter is becoming a fairly consensus type of position.
>
> There could be an argument, and I am not going to make it here, that
> progressive and stable might be defined as relative to the slope that
> is being developed in the COMET study.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: Yes, I think that the slope in the COMET study is very
> convincing. As I was looking at this before our discussion, I was
> thinking in my own mind what would be that alarming rate of
> progression that causes the parents to be very concerned, and that
> would be a diopter or more a year. Those parents call you. They call
> you three times the first week after the visit. So, that would be the
> alarming level. But for a cut-off to consider for this study and find
> out what is going on, I would say 0.5 diopter or more per year and
> stable would be less than that.
>
> Regressing\--it is interesting, I would say in children at 10 years I
> have probably had three or four kids where, seeing them biannually
> perhaps, they have gone down 1 diopter, 1.5 diopters, 2 diopters, and
> I have done the refractions. We are talking cycloplegic. There are
> definitely kids that regress but it is a handful. So, if you wanted a
> definition of that for that odd-ball group, which you probably won\'t
> even see in your study, over a two-year course reduction of at least
> 0.75 diopter or more.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: With the term stable I have a personal bias I guess. I
> have never liked studies that have patients getting worse and they
> call them stable. To me, stable means things are okay, not changing. I
> might even request a different word use if you want to track people
> along an acceptably worsening line as being non-progressive. But it
> seems like there is a consensus. I kind of agree with the 0.5 just
> because I think with less than that it might be hard to measure
> reliably. If you have somebody starting at age 6 with 0.5 diopter a
> year, they are probably going to be a high myope by age 16 anyway. So,
> it seems reasonable to consider 0.5 diopter as the progression point.
> I don\'t have a comment really on regression.
>
> DR. GATES: Any other comments on question one? Dr. Bullimore?
>
> DR. BULLIMORE: I like Dr. Miller\'s addition of, if you like, the
> rapid progressor. If the agency wanted to add that to its
> classification, I think that is reasonable criteria.
>
> DR. GATES: Any other comment on number one? If not, we will move on to
> number two, is there an accepted evidence-based baseline
> characterization of patients who are at high risk of developing
> progressive myopia? First off, do we need Wiley to say what he is
> looking for in this question or to expand it before we get started?
> Would you like to do that, Wiley?
>
> DR. CHAMBERS: Again, this is more a definition type thing. People will
> say, you know, we want to enroll people that are high risk and we
> don\'t have common definitions for what high risk is. So, if there
> currently is a consensus, we would like to know what that is or if you
> think there is a current range of what that is. If not, we can
> ultimately leave it to individual protocols. But, again, to the extent
> that we can use common terms and people have ideas of what those mean,
> we would like to know about them.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: So, since you have used the phrase progressive myopia,
> should we use the criteria for progressive that we have just defined,
> or are you looking at some other type of myopia here? Are you looking
> at people who are going to have rapidly progressing myopia or just
> common or garden 0.5 diopter per year myopia?
>
> DR. CHAMBERS: We will take whatever you give us.
>
> DR. BULLIMORE: Splendid!
>
> DR. GATES: All right, let\'s go around the table again. Dr. Plott?
>
> DR. PLOTT: I think that there would be probably a check list in other
> conditions I am familiar with. For example, in atopic dermatitis there
> is a check list of things that define people who are at high risk and
> sometimes it is getting, you know, two out of three or a minimum
> number. But the things that we have heard seem to be convincing,
> positive family history and age of onset being important factors,
> maybe not the only factors but elements that are important to view in
> a clinical trial.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I would agree with Dr. Plott that there is nothing from the
> American Academy of Ophthalmology that says who is going to develop
> myopia but we know from the data that is there that if the child
> already has myopia, they are at much higher risk of developing
> progressive myopia than a child who doesn\'t. Likewise, a child who
> has at least a mother and maybe a father\--with 90 percent
> certainty\--that has myopia they are at higher risk than a child who
> doesn\'t. So, the high risk characteristics would then be already
> having myopia and having a positive family history.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: Because myopia is a failure of the emmetropic gene, as
> we all know, if you stop 100 people in the street who are perfectly
> visioned, 20/20, you would expect that all the optical elements would
> be the same and the arrangement would be the same and, to your
> astonishment, they are all over the lot. So, there is a gene
> responding to the blur circle being presented to the retina. At birth,
> with the early plasticity of the organism, that starts to rearrange
> the optical elements and this is what is wrong in myopia. This gene is
> somehow asleep or somehow impaired. A child is born with the normal
> amount of hyperopia. I think we all agree to that. I think that if you
> see a rapid loss of normal hyperopia in the very, very young child
> with a parental history of myopia, that would be someone who is at
> high risk of developing progressive myopia.
>
> DR. BULLIMORE: At the risk of being repetitive, somebody who is
> already myopic, they are going to progress. I think that is one of the
> few certainties in eye care that we can rely on. Certainly younger age
> and parental history are in there. As far as the people who aren\'t
> yet myopic, Dr. Zadnik and her colleagues, as mentioned today, have
> shown that the people who have less than 0.5 diopter of hyperopia at
> the age of 8 are more likely to become myopic than those who have more
> of a hyperopic buffer. So, that is it.
>
> DR. CHEW: I don\'t have much more to add, other than what was said
> already, younger individuals who are already myopic and perhaps with
> the genetic factors of the family being involved. I am not sure in
> terms of any lifestyle in terms of close reading. It seems that all
> the children are playing Game Boys and doing other things. So, I
> don\'t think we can differentiate them that much at this
> point\--perhaps in other cultures. I think those are the key features
> that we have identified.
>
> DR. FEMAN: Well, I have to agree with everyone so far, but I need to
> point out some things that have already been included in the
> discussion. I don\'t recall whether Dr. Gwiazda or Dr. Zadnik pointed
> out that the key thing in their studies was whether or not the child
> was myopic at the beginning. It didn\'t matter what the genetic status
> was or the family history. I think Dr. Gordonson highlighted that
> also. So, I think the child actually defines what is going on, the
> child that you are looking at. So, a child that is myopic, well, how
> much is myopic? Dr. Bullimore mentioned perhaps 0.5 diopter, and
> earlier people said at a very low level and it is very difficult to
> measure it. So, I would define what you are asking in question number
> two as a child already having one full diopter. That way there is no
> uncertainty in your mind that the child has myopia and progresses at
> 0.5 diopter a year so that child was already 1 diopter myopic and has
> gone on in a year to another 0.5 diopter more myopic. By all means,
> that should be a child that is at high risk for developing progressive
> myopia.
>
> DR. BULLIMORE: So, what you are saying is that they need to be 1.5
> diopters\--
>
> DR. FEMAN: Before they enter the study.
>
> DR. BULLIMORE: Yes. I think by the time they get to a diopter we have
> probably eliminated any possibility that it is a measurement error
> and, particularly if they are young, there is a high probability that
> they will progress. I don\'t want for us to be unnecessarily
> burdensome and say you have to follow people for a year or two years
> before they can be enrolled trial. So, while I agree with your 1
> diopter criteria, I don\'t necessarily agree with the need to document
> progression prior to enrollment and randomization in a randomized
> clinical trial.
>
> DR. FEMAN: I agree with you. Thank you.
>
> DR. GATES: Myself, I believe those that are high risk are especially
> ones with presentation at the younger end of the spectrum. From the
> data, those seem to be most likely to be at very high risk in the
> higher amounts of myopia.
>
> DR. GORMAN: I have nothing to add.
>
> DR. MILLER: I agree with the minus 1 diopter criteria. Perhaps,
> though, looking at the COMET data there would be an even lower level
> inclusion criteria for the older kids. I don\'t know. As you were just
> mentioning that, I was thinking in a 12 year old that is minus 0.5
> that previously was somewhat hyperopic that would also be a
> progressing kid, I would predict. But the minus 1 diopter is a clear
> endpoint to go with.
>
> DR. STEIDL: First of all, there are a lot of conditions\--Dr. Miller
> was alluding to this earlier\--a lot of conditions that predispose to
> myopia that you probably want to exclude. The list is pretty long
> although it is not maybe highly prevalent. It involves connective
> tissue disorders and kids with ROP and many metabolic abnormalities.
> In general, I think people with any kind of RPE disease have a
> predilection to developing myopia. You might want to exclude that.
>
> I agree with the minus 1 diopter. One of the papers has a plot of four
> typical children with myopia and one kid with about 1.25 and never
> went worse. I just bring up that I think there are kids that do that.
> But it seems to me that this has to be derived from the data that we
> are looking at. It may alter at a different age but it sounds pretty
> reliable that a specific refraction at a specific age is highly
> predictive. You add to that if you have siblings and parents involved.
> But in general I think the minus 1 diopter sounds good to me.
>
> DR. GATES: Any more comments about question number two? If not, we
> will adjourn for lunch. We will meet back promptly at one o\'clock.
> For the members of the committee, there is a table reserved in the
> back of the restaurant for lunch. Thank you for your comments,
> questions and debate this morning.
>
> \[Whereupon, at 11:52 a.m., the proceedings were recessed for lunch,
> to be resumed at 1:00 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. GATES: At this time I would like to reconvene the drug advisory
> committee for Dermatologic and Ophthalmic Drugs. First off, we are
> going to have the open public hearing time again. It was initially
> announced at one o\'clock, so earlier when we had the open mike time
> there might have been some folks who were planning on coming exactly
> at one o\'clock. So, if there is anyone who would like to make a
> comment, would they proceed to the microphone?
>
> \[No response\]
>
> Thank you very much. We will proceed with our discussions of the
> questions. So, question number three, which populations should be
> studied prior to approval of a drug treatment for prevention or
> retarding myopia?
>
> Since this is a different session we will start over to the right, if
> you would, Dr. Steidl.
>
> DR. STEIDL: Well, addressing what we have here, going (a), (b), (c),
> (d), I am just referring to some graphs that are in the handout and it
> seems that the active time is in 6-7 years to 16. It seems to me that
> the most active time period is probably around age 9 or so. So, I
> would be inclined, just looking at this, and this is a fairly
> arbitrary comment, to shoot for something in the 9-12 range. But I
> would be very open to other people\'s comments.
>
> As far as the other issues, in general it seems to me that we would
> like a cross-section unless, as we discussed before about the ethnic
> groups, there is some data to suggest that it is not needed. So, as
> far as educational levels, you might want both less educated as well
> as more educated. I would be inclined to have a cross-section of
> Hispanics, African Americans, Caucasians and others unless there is
> data to suggest that that is not needed. Of course, you would want to
> study those with a family history of myopia as well as those without,
> it would seem to me. The other defining characteristics are things we
> have mentioned before, such as various diseases, ocular diseases,
> systemic diseases and other things that could impact on myopia. I
> would want to exclude them.
>
> DR. GATES: Thank you. Dr. Miller?
>
> DR. MILLER: It seems as though you want to try to know whether you can
> apply this drug broadly to healthy kids. It sounds as though really
> the defining issue is degree of myopia and the younger age group when
> they start progressing the fastest.
>
> They should make an effort to study a variety of\--to mimic the U.S.
> population but I don\'t think we have to target specific groups to
> answer that question. If they want to have a group that has
> progressive myopia, then they should make sure they include some Asian
> groups. But myopia is found in Hispanics and Caucasians and blacks but
> I don\'t think they have to target the ethnic groups because we are
> looking at similar outcomes when it does occur, except for the Asian
> group which may tend to have a more alarming rate.
>
> This perception that we have that family history makes a difference,
> it sounds like there are some other studies disputing that and if they
> just start out with significant myopia, we may just be able to make it
> simple and go with that.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I am going to echo some of Dr. Miller\'s comments in the
> sense that I think this study should be age front-loaded, and 6-12 in
> my opinion is perhaps a little broad in terms of the group that is
> most likely to gain the most benefit from this. So, I would probably
> wish to start recruitment in the first graders. If the incidence is 25
> percent in the United States population, that would give you 250,000
> potential subjects per year. No matter how large a clinical study
> needs to be, that should give you enough to recruit an adequate number
> in a rapid period of time.
>
> Educational levels and ethnic groups are going to be represented by
> your study sites. The family history of myopia, I think they will be
> over-represented in any study because I think there will be a
> motivated subpopulation who will be seeking treatment. So, I don\'t
> think you will need to recruit for them. In fact, it may be difficult
> to statistically correct for them.
>
> Other defining characteristics, I can understand for the clarity of
> the data and interpretation why you would want to have a population
> with no other ocular disease but, just to play the devil\'s advocate,
> you might want to see whether it prevents progression in other
> diseases as well that also are confounded with myopia.
>
> DR. GATES: Thank you. Myself, I am very interested in the 6-10 year
> old population from reading the background information, probably more
> than from 9-12\--the younger folks.
>
> Education levels and ethnic groups and family history I think just
> need to echo the U.S. population. Family history I believe will bear
> out as the numbers are looked at.
>
> DR. FEMAN: Well, I sound like I am just echoing what you have already
> said but, again, somewhat front-loaded. Although this disorder
> continues to progress until the children are 16 or so, I think you
> really want to look at a younger age range when this is just starting
> out. We have already talked earlier this morning about having children
> initially getting into the study when they are almost a diopter
> myopic. So, I think that will define the population quite well.
>
> Whether or not there is an education level or particular ethnic group
> or family history, those are all interesting asides but I don\'t think
> those will really affect what the results are with this.
>
> Other defining characteristics\--earlier this morning people talked
> about ruling out other retinal disorders and things like that, but
> that is a standard part of any type of drug trial. Providing other
> disorders are ruled out, there should be no problem. So, 6-9, 6-10, in
> that range.
>
> DR. GATES: Thank you. Dr. Chew?
>
> DR. CHEW: I would agree with what has been said already. I think the
> earlier the better in terms of event rates. It sounds like these
> people may actually progress a lot more rapidly and you may get more
> events with that. On the other hand, you want to be generalizable so
> that you would be able to see if people who already have myopia of 1
> diopter by the time they are 12 years old, would they still benefit
> from it. So, from that point of view, you may want to extend it from 6
> to 12 for that reason.
>
> What has been said already, I agree with the educational level, ethnic
> groups and family history having no bearing. We don\'t need to
> stratify at least by those issues.
>
> Again, I think systemic diseases and other optic diseases\--as Steve
> said, these are just natural for clinical trials and we would try to
> exclude those patients. It may be too small a number to do any subset
> analysis on so it is best to go with that general group.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I am in violent agreement with most things. I think
> 6-12 is reasonable but I think any sponsor should be cognizant of the
> fact that David Gossen and his colleagues have indicated that in girls
> myopia tends to stabilize around the age of 13 and a little later in
> boys, for obvious reasons. So, I would certainly be nervous about
> recruiting too many 12-year old girls into a study given the fact we
> wouldn\'t expect them to progress much beyond that age.
>
> A couple of other things, the group from Novartis proposed that
> astigmatism be a consideration. I have no strong views on that but I
> think avoiding anisometropia of more than a diopter, strabismus and
> enrolling people with 20/30 in each eye are perfectly sensible things
> to do.
>
> DR. GORDONSON: I think I would separate to get different groups. Also,
> the starting out group, the first graders and the ones that are very
> active, 9, 10, 11 and those there are slowing down, or other groups.
> And, the family history is important and I have no other additions to
> the defining characteristics.
>
> DR. WEST: I agree with what has been said so far, but I would point
> out that in Table III in the blue handout, as well as the top slide on
> page 8 of the Novartis material, although patients who present with
> myopia at a younger age end up with a higher degree, in fact, if you
> just assume a straight line progression, the rate of progression for
> the younger children is only 0.6 diopters per year while that of the
> 13, 14 and 15 year olds actually ends up being 0.85 to 1.15 diopters
> per year. So, in fact, assuming that the younger children have a
> steeper progression is not borne out by the Mantyjarvi data.
>
> So, I think that one of the nice things about including the younger
> group is that it gets around some of the differences in consent issues
> per site, for the practicalities, and it also obviates the potential
> issues for surveillance for pregnancy in menstruating females which
> could be difficult socially for girls who would need to undergo
> pregnancy testing perhaps as frequently as every month. That could be
> a significant barrier for enrollment.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: I think the important thing to think about is the disease
> that is being considered for the indication and that the population
> should reflect that disease. So, whether it is in a subpopulation of
> patients found only in a small number of individuals or can be cast by
> a variety of different ages, it should reflect those people.
>
> I think Dr. West has made an important point that in addition to age
> of onset, it is maybe the duration with the disease that may be
> important with regard to the progression of the disease. So, the age
> is certainly important and younger sounds, to me, better.
>
> I am not sure what educational level would impart but ethnic
> population, again, ought to reflect the disease population. Of course,
> the family history is important. One of the other characteristics I
> might add that could be important, thinking about the long-term, is a
> family history of myopia with an associated pathology that comes later
> that has been mentioned\--retinal detachment, retinal degenerative
> changes and glaucoma. If there is that combination of association in
> the family history, it could be instructive in long-term studies of
> these patients whether by the course of treatment they have they
> avoided some of these longer-term associated conditions.
>
> DR. GATES: Dr. Chambers?
>
> DR. CHAMBERS: I would like to go back and clarify two particular age
> groups just so I know we haven\'t skipped over them. There has been a
> lot of discussion about earlier is better and if it works in one age
> group it is likely to be used in another age group. I want to make
> sure that the committee is not suggesting that we not initially
> studying 3-6 year olds. Obviously, it is possible to determine where
> they are in refractive stage and if they are not at the hyperopic
> level you might expect that people may infer that they are headed down
> that path. But if that is a group that you think is better to study
> later and not to study early, before approval, specifically I would
> like you to comment on that.
>
> The second is an age group that we haven\'t talked about much today,
> and that is the 20 to 27, 30 year olds who are typically post high
> school but in college who develop a low end of myopia. They tend to
> act differently than what we have mostly been talking about this
> morning. Is that a group that you would think should be studied prior
> to approving a product for this?
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: Just from a practical point of view, as far as the very
> young subjects, there are likely to be very few under the age of 6.
> One might say, well, these are a different group altogether. I guess
> it also depends on what the sponsor is seeking in terms of an
> indication. If they were seeking some claim of prevention or delay of
> onset, then obviously it would behoove them to recruit children before
> they were myopic, maybe those considered to be at high risk based on
> family and sibling history. But if we are just talking about slowing
> down the progression myopia, then it seems pretty fruitless to go
> below the age of 6 just in terms of the age of incidence.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I would agree with that. My general impression in this
> loss of hyperopia group that I follow, because I see a lot of former
> premies and I keep a good eye on them because they are supposed to
> develop myopia in a large amount, is it seems just kind of variable. I
> will have kids where it is a little bit less and then when I look at
> the family history I don\'t feel as though it tells me\--I don\'t
> think we would have as neat and clean defining ways to find a group
> and this should be studied secondarily. It is a very interesting
> question, can you prevent it from occurring or can you slow the
> beginning? I mean, a diopter is a lot for that first diagnosis, but
> not as a first pass, in my opinion.
>
> The other question about the older people who are stable and then
> suddenly develop myopia, as a resident I always thought that it would
> be great to study a group of people going to law school and test them
> at the beginning and end of law school. You know, they have been
> stable for a while and you get a constant statement about sudden
> progression during law school of myopia and they have been stable. So,
> I wish we had a way to quantify percent of the day you spend doing
> near activities and have that in some sort of clinical trial that we
> are doing, but I don\'t see any way to do that. So right now, no, I
> would stick with 6 to 10, 12 year olds.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I actually study adults and adult myopia progression
> but I do think, from the point of view of pharmacological
> intervention, it would be a very difficult group to study because the
> progression rate is so low. You could try and enroll a group of law
> students who, as Dr. Miller suggests, do progress quite a bit but, you
> know, college age students seem to have different things on their mind
> and I would be worried about compliance and things like that. Again,
> it is up to the sponsor I guess what indication they want.
>
> DR. GORDONSON: If you are going to study law students, if they are
> minus 3 they are exerting no accommodative effort at all and if they
> progress that is an interesting group. So, I would look at that
> with\--I don\'t know, a jaundiced eye, something like going to law
> school and not going to the ophthalmologist and finally going at the
> end of three years\--I don\'t know. But, certainly, if you get to
> minus 3 you are not exerting any accommodative effort.
>
> DR. GATES: Dr. West?
>
> DR. WEST: For clarification, you mean you wouldn\'t exert any
> accommodative effort if you were reading without correction?
>
> DR. GORDONSON: Well, we are assuming they are going to read without
> their correction. If they spend 12, 15 hours reading, I assume many of
> them will read without their correction.
>
> DR. WEST: Many do, a lot don\'t though I think.
>
> DR. GATES: Wiley, is that enough discussion on number three?
>
> DR. CHAMBERS: Yes, thank you.
>
> DR. GATES: Right, we will go to number four, what is the minimum
> baseline level of myopia and/or a baseline set of associated factors
> that might justify a pharmacological intervention to arrest its
> progression? Wiley, would you like to preface number four with any
> remarks?
>
> DR. CHAMBERS: I think you started down this path earlier in some of
> the discussion but I think I would just like to see that fleshed out.
> Thank you.
>
> DR. STEIDL: I am not sure I have much to say. I think the minimum
> refractive error rate\--if I am understanding the question correctly,
> a lot of us are thinking that minus 1 would be appropriate. I think if
> you pick that a lot of the other things will just fall into place and
> it is not a big enough study to separate out a lot of these other
> issues probably.
>
> As a retinal specialist, I am extremely interested in axial length
> with regard to progression, but in terms of how that affects the
> baseline level selection, I am not sure that it is that relevant to
> me. You wouldn\'t want someone with corneal disease. I don\'t know how
> many 6-year olds have significant corneal disease but, again, I would
> exclude anyone with that but, that being said, the cornea isn\'t a big
> issue for me personally either.
>
> The period of time for changes to be observed, I am not sure I
> understand that. Is that the period of time before enrollment? Was
> that the issue?
>
> DR. CHAMBERS: It comes back to the issue of stability and if you
> measure somebody do you want to measure them again a month later, or
> do you want to measure them again a week later and make sure they
> really are at that particular point? This is all entry criteria.
> Again, we get a little more into question five, it is truly looking at
> rates. Obviously, in writing the questions ahead of time we weren\'t
> sure which way the discussion was going to go. We didn\'t know whether
> the committee would ultimately think it was better to pick particular
> entry criteria based on a single observation or based on a rate. So,
> we wrote both questions. You tell me what you think.
>
> DR. STEIDL: Yes, I think it would be just simpler to pick a refractive
> level of, say, minus 1 and just stick with that and not expect a lot
> of prior evaluation. I am curious what other people think.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I think we have discussed this before and the minus 1
> criteria is something that we have settled on. I would say that if I
> saw someone with 0.5 diopter of myopia and at the last visit they had
> been plus 1, I would also say they fit the sense of the inclusion
> criteria but that would have to be flushed out differently and the
> sponsor will not have trouble finding patients for this study so there
> is probably no reason to go to that level of extra work.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I would agree with the 1 diopter. Going back to the
> glasses analogy, if you put on glasses and they make a dramatic change
> for someone, then that would be somebody whom I would consider
> enrolling in a study.
>
> The concern about progression though, I am not clear in my mind yet,
> from the data that has been presented this morning or the data that I
> read beforehand, what fraction of children will be needlessly treated
> if they are in the stable group. So, if you are 1 diopter at age 6,
> your chances of progression are 90 percent or 80 percent or 70
> percent, and since I don\'t have a good handle on that it would give
> me pause until I had a better handle on that for what number of
> patients or human subjects would be treated for no benefit. So, I have
> this desire for either knowing the progression rate so I know that
> number or having a progression rate put into the entrance or
> eligibility criteria.
>
> DR. GATES: For myself, I am very interested in axial length, although
> I would have to defer to my pediatric colleagues to know where to set
> the number. I am more interested in the change of axial length from
> entrance into the study and its conclusion. I am very interested in
> that. As far as where to set it, I would have to defer. The minus 1
> refractive error point I am very comfortable with. Corneal
> curvature\--I think it should be looked at but I don\'t feel like it
> is going to tell us as much as the other variables.
>
> DR. FEMAN: I seem to be repeating everyone again but let me make some
> points on this. First of all, someone, and I think it was Dr.
> Chambers, talked about the section (d) period of time for changes to
> be observed. I think that becomes a key issue in many ways in that you
> don\'t want a child perhaps coming in and being examined and being a 1
> diopter myope first and then 30 days later being something else,
> perhaps less, and maybe it is a testing phenomenon. So, I would think
> that for enrollment in a study such as this any child would have to
> have two exams confirming these features before they embarked on three
> years or so of being on an investigational drug. So, I would think
> that as part of the beginning of the study it might be best to have a
> child have an exam and then come back within 30 days or 60 days, or
> whatever we would all agree upon, for a repeated test confirming that
> that is what the findings truly were. That is the first thing.
>
> The second one is that I don\'t know what the real data is, normative
> data for axial length for children in the 6-9 age range. I know what
> it is for adults, for people 20-30 years of age. And, I don\'t think
> there are really good criteria and this would be a great way to find
> it, using this and looking at the data for all of these children. I am
> sure we can get ultrasonic measurements of the axial length but that
> wouldn\'t be what brings a child into the study. What would bring a
> child into the study is the minimum refractive error, and I think we
> have all agreed so far, I think, as minus 1 being a standard to start
> with.
>
> Corneal curvature\--wouldn\'t this be an interesting phenomenon to
> study? Again, it is not part of the study. It is not really directly
> related to the question but I don\'t know what this investigational
> drug does to corneal curvature over a two- or three-year period, and I
> don\'t know if the manufacturer representatives know that either. It
> would be interesting to find out if there is any change.
>
> DR. GATES: It could bear out, Steve, to be a factor like corneal
> thickness in the ocular hypertensive trial. It would be very
> interesting to follow. Dr. Chew?
>
> DR. CHEW: I think I am just echoing what everyone said as well. You
> have to look at the practicality of doing a trial and you have to
> decide whether the patient is going to come and have all these things
> done. It takes time. These are working parents usually so you have to
> be careful you are not making it so heavy that it is not very
> practical.
>
> On the other hand, axial length is I think very interesting,
> particularly in terms of what happens with the corneal/retinal changes
> in the end. So, that should at least be in a subset of patients. I
> think the same is true of curvature. You may not do it on all patients
> but I think you should have some data on this subset. Again, I think
> the minimum refractive error would be one that brings the patient in
> and 1 diopter seems to be very reasonable to do.
>
> I guess I am concerned about Steve\'s comments on the reproducibility
> of this. We have been refracting patients for a long time. So, I just
> wonder how much reproducibility data do we have and is there enough
> from other trials to really know do we need to have almost a
> qualifying visit and then a randomization visit again that adds to the
> burden to the study. So, I think it will have to be, again, the
> sponsor\'s prerogative to look at this more carefully.
>
> DR. FEMAN: I wasn\'t questioning reproducing the data as much as
> questioning whether or not the child was adequately cyclopleged at the
> time of doing the refraction. So, if you can do two tests to show that
> your cycloplegic refraction was identical, that would confirm it.
>
> DR. BULLIMORE: Minimum axial length, unnecessary. Minimum corneal
> curvature, unnecessary. Minimum refractive error, minus 1. Repeat
> visit, we don\'t do that for our study and we enroll people based on
> the cycloplegic refractive error. It is adults but I don\'t think we
> should do it for kids.
>
> I am worried, like Dr. Chew, about respondent burden. Period of time
> for changes to be observed, I think the data are out there so if you
> were to talk to Dr. Gwiazda, Dr. Zadnik and other people who have
> natural history studies in myopia and say, okay, if you had subjects
> at a given time point who were minus 1 or more how many of them are
> likely to progress, they would be able to provide that data. I think
> that, given these fine scientists who work with this particular
> sponsor, they would be able to come up with a rationale for probably
> not doing a two-time point eligibility criteria. If they are minus 1,
> they are in. If they are not going to progress, then that is going to
> limit the power of the study so I think it is in their interests to
> ensure that my impression is borne out by the data that exists in
> their vaults.
>
> DR. GORDONSON: Being that you could find practically any axial length
> in the normal eye, the issue is that the emmetropization, again, which
> is failing\--I don\'t think axial length is important. Minus 1 is
> good. I think the cornea is minimal in this. Time to be observed, I
> would say a year.
>
> DR. WEST: Minimum axial length, I would say probably not needed unless
> you were worried that somebody had refractive emmetropia and I think
> that that would help to actually weed some oddballs out, for instance,
> children who have significant ROP and develop myopia. It is not an
> axial myopia, it is a refractive myopia so it would be a safeguard to
> keep the population more clear by having a minimal axial length, that
> you had to have an axial length above a certain length.
>
> I was thinking about corneal curvature not in terms of minimum but in
> terms of maximum, and that would also help to give you a more purely
> axial myopic group rather than a combination of axial and/or
> refractive. The minus 1 refractive error seems fine with me. The
> period of time for changes really depends on what you hypothesize the
> drug\'s effect would be compared to the natural history, and the data
> so far seem to suggest that a two- to three-year time period is
> necessary.
>
> The other idea that I had about the two enrollment visits that would
> be needed is that you could assess accommodative amplitude prior to
> cycloplegia and then after cycloplegia and make sure that there was
> accommodative paresis from the cycloplegic agent.
>
> DR. PLOTT: For enrollment at baseline for a protocol, I would think
> you would need some level of disease present in combination with the
> age. There seems to be association there, particularly given the time
> frame. I would leave most of these questions to the experts but depend
> on the data regarding the period of time that we need to look at,
> although I think it could be a short amount of time that you need
> prior to baseline.
>
> DR. GATES: Any other discussion or comments on question four? If not,
> we will proceed to question five, what is the minimum amount of change
> that would justify a pharmacological intervention to arrest its
> progression? Dr. Bull?
>
> DR. BULL: I just wanted to ask people here for comments on the period
> of time of changes for changes to be observed. Wiley, was that
> intended as an interval?
>
> DR. CHAMBERS: Basically, I heard most people saying they just wanted a
> single visit; a couple of people saying they wanted some kind of
> repeated, whatever.
>
> DR. BULL: My concern was if we are looking at progressive myopia and
> how long the diagnosis had been established, what I am not clear on is
> whether or not if a child presented to an office first visit with
> myopia of 1 diopter, is that a sufficient criterion for entry in the
> study or would there need to have been a past history of having
> established a diagnosis and moving up to 1 diopter.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: My impression, without having hard numbers, is that if
> somebody shows up at the age of 6, 8, 9 or whatever with minus 1 in
> recent history they were probably less than that and in the future
> will be more than that. I think you may be able to glean from the
> patient\'s symptoms that there has been an onset of myopia by
> some\--you know, not having difficulty seeing the blackboard and all
> of a sudden having difficulty. But, again, in terms of respondent
> burden, I think I lean toward if they are minus 1 in your chair, then
> they are in.
>
> DR. BULL: I guess I am still not entirely clear on the response from
> the committee as to where you are on number one with progressive
> myopia and the increase of, you know, 0.5 or greater for classifying
> the myopia. I guess in terms of entry criteria, are you establishing
> that it is sufficient? You just want a diagnosis of myopia without a
> qualifier on it as to whether or not\--
>
> DR. BULLIMORE: That is why I asked the question when the issue was
> raised. Are we defining these from the point of view of entry
> criteria?
>
> DR. BULL: Entry criteria, yes.
>
> DR. BULLIMORE: So, I can say progressive is at least 0.5 diopter over
> a year, but I can then turn around and say but I don\'t think that is
> necessary as an entry criterion. That is kind of where I stand on
> that.
>
> DR. WEST: And I think perhaps the confusion arises from comparing
> adults to children, and it is apples to oranges because in adults
> myopia is typically stable and if there is progression you need to
> define it. But, by its very nature, myopia in a 6-year old is
> progressive, or almost always is. So, the idea of needing to observe
> progression before making the diagnosis\--we assume that myopia in
> children will be progressive.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I definitely agree with that, and I would say that the
> ones that don\'t progress are almost shocking. You follow someone who
> stayed at 1.25 for four years and you will discuss it with the family
> you are so surprised it happened. You might say, conversely, that if
> you had someone who was minus 1 and you knew a year ago they were
> minus 1 you might exclude them because they are so unusual. But just
> to have them show up as minus 1 on a new diagnosis, the chances are it
> is going to progress.
>
> DR. GATES: Any other opinions on that to the contrary? We are all in
> fair agreement there. All right, let\'s proceed to number five.
>
> DR. STEIDL: If this is a question that is, again, for entry criteria,
> I don\'t think that the axial length is ultimately an issue. Again, if
> this is entry criteria I am not sure that we need to calculate a rate
> prior to entry. So, I guess it is not relevant then. The same with
> corneal curvature, I guess (d) also.
>
> DR. GATES: Wiley, do you need us to go around the table on number
> five?
>
> DR. CHAMBERS: Only if there is anybody that disagrees.
>
> DR. BULLIMORE: Are we talking about progression now and we are no
> longer on entry criteria?
>
> DR. CHAMBERS: We are saying progression as an entry criterion, whether
> progression is necessary as an entry criterion.
>
> DR. BULLIMORE: Ah!
>
> DR. CHAMBERS: If you change your mind now\--
>
> DR. BULLIMORE: Immovable!
>
> DR. GATES: All right, let\'s proceed to number six, what is the an
> ideal refractive error or range of refractive errors?
>
> DR. BULLIMORE: Well, I am a minus 6.25 and I think that is pretty
> ideal.
>
> \[Laughter\]
>
> DR. CHAMBERS: This is meant as a final goal, what should we be trying
> to get people to?
>
> DR. STEIDL: Just going by the tables in here, there is a big jump in
> that minus 5 to minus 7 range. It went from\--I don\'t know what it
> was, something like 3 or 4 to something like 11. So, I think when you
> are getting around to that 6 diopter range the pathologic changes do
> start to kick in, it seems to me. So, again, at this point although I
> am very interested in changes in axial length, I don\'t know how to
> quantify that at the moment. So, I would say minus 6 diopters
> probably. Actually (b) is a rate of change. So, rate per year, is that
> what we are talking about?
>
> DR. CHAMBERS: No, we are on question six. From the original background
> package there were a couple of questions that were switched in order.
> The questions are the same but we just switched the order to group
> some of the baseline questions and put them together and some of the
> other endpoints to make it easier to flow for this discussion.
>
> DR. BULLIMORE: This is really one for the philosophers. I mean, we
> could say I kind of like my 1.5 but would I like more? Maybe.
>
> DR. CHAMBERS: Okay, if you get to recreate yourself, what would you
> like to be?
>
> DR. BULLIMORE: A little hairier.
>
> \[Laughter\]
>
> DR. CHAMBERS: With respect to refractive criteria?
>
> DR. GATES: Go ahead, Dr. Miller.
>
> DR. MILLER: I will tell you what I would say for the answer, minus 1,
> plus 0.5 at 90 because I guess you get a little depth of field too.
> Right, if you could pick it? But this is a real question though. The
> question is what is considered bad? You know, what do we consider bad
> enough so that you would let your child be in a protocol? So, what do
> we want to stop? Is it the cosmetic issue of the glasses or is it that
> at a certain point we consider it is unacceptable to be beyond a
> certain amount myopic? So, it is getting at a real question.
>
> But my problem is defining when I would let my child be in a trial.
> So, if I had a child who came in with minus 1 and I had a history of
> progression of minus 1 over one year, there is no question I would put
> them in a trial. But that is what we are considering the rapid
> progression group so I guess that is an easy one. Then the question
> is, you know, in the progression group what would be reasonable. The
> sponsor wants to present it in a fashion so that their medicine will
> be widely applicable but, on the other hand, is it reasonable? I,
> personally, don\'t know enough about the medicine and the potential
> side effects. We are getting ahead of ourselves a little bit in trying
> to define what is a risk versus benefit sort of thought process here
> because if you are talking about rapid progression I feel comfortable
> giving you a number on that, but I don\'t feel like I know enough to
> do the lower level.
>
> DR. CHAMBERS: Let me try rephrasing it another way. Say we could give
> you a single drop and it would change your refractive error to some
> number, and two drops get you this, three drops get you this, one drop
> gets you this and that would get you a number. What number should we
> be trying to get people to?
>
> DR. GORDONSON: Plano in one eye and minus 0.75 in the other.
>
> DR. MILLER: That is brilliant.
>
> DR. BULLIMORE: let me take another stab at this. I think really this
> is kind of a little foreplay for question seven. I think when you look
> at the risk of some of the nasties that happen in all eyes, you have
> more risk if you got more myopia. I think, you know, less is clearly
> better. I think if you got somebody who, based on their age of onset,
> is destined to be a minus 5, then with many, many years of treatment
> of you could hold them down to a minus 2 or minus 3, then that would
> be worthwhile. I think there is a difference between being a minus,
> say, 1.5, which is what I am normally, and I wouldn\'t want to be
> anymore myopic because 1.5 is kind of perfect for my computer. As a
> presbyope who has yet to come out of the closet\--
>
> \[Laughter\]
>
> \--I am quite happy at that distance but wouldn\'t want to be 2.5
> because I probably wouldn\'t be able to see my computer comfortably
> without correction. So, I could think about how we function in the
> distance, how we function at intermediate but I think if we can
> minimize the amount of myopia then we are minimizing the disability
> that people experience without their correction. We minimize the risk
> of detachment and other stuff and, I will throw it on the table now,
> if you talk to a friendly refractive surgeon, you know, a minus 3 is
> easier to deal with than a minus 6. So, there are a range of benefits
> but drawing a line in the sand and saying this is the best one is
> tough.
>
> DR. CHAMBERS: If you take it to the full extreme though, less myopic
> means you end up being hyperopic. Would you rather be minus 0.5 or
> would you rather be plus 1?
>
> DR. BULLIMORE: Looking at my future years, I am minus 1.5 now but if I
> believe the literature I will be ametropic by the time I am 65 or 70.
> So, I am quite happy being a minus 1.5 myope because that is my
> future. If I was ametropic at this age, which people of my age who
> have had LASIK are, they are going to be hyperopic and relatively
> miserable when they get into their 60s and 70s because they will be 1,
> maybe 2 diopters hyperopic. So, again, I think a little bit of myopia
> is okay but keeping it under control I think is a worthy goal. So, I
> would rather be myopic than hyperopic, in answer to your question.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I think this is the argument that all conditions rather
> than diseases faces, how much of a condition is a bad thing? If you
> are an obsessive-compulsive but functionally become a physician\--
>
> \[Laughter\]
>
> So, I think that one of the criteria that the sponsor and company seem
> to measure is issues about quality of life, and I think we have all
> danced around that without being willing to say it. That is, if you
> are 6 years old and can function in school okay without your glasses
> but better with your glasses, so they were helpful but not essential,
> I think we would all be pretty happy with that definition. I don\'t
> know how to put that into a regulatory guidance or a protocol
> statement or an outcome variable, but I think it is the same thing
> that I feel right now with my progressive farsightedness. I can carry
> glasses around as a crutch so I can use them, but in a pinch I can
> read a page without them. So, I am happy to have them to help but I
> don\'t need them yet. In five more years I will need them. So, where
> are the drops for me is what I really want to say, as opposed to this.
>
> The other issue is the trade-off for what are you looking to give up
> in your life for this change of refractive error? I think we have the
> answer if it is a one-time intervention such as surgery. I have think
> we have a dollar value that people are willing to pay. It is hard for
> me to decide if the increase in LASIK surgery is because the price has
> plummeted, therefore, it is on sale, or if it because more people want
> it. Or, did all those people really want it and now they can just
> afford it. So, there will be a pharmacoeconomic discussion that will
> go inside the company, inside the country and, you know, at the family
> kitchen table as to whether this is worth fewer years in glasses or
> fewer changes in glasses. So, I think there are a couple of ways to
> say the ideal refractive error.
>
> DR. GATES: Dr. Bull?
>
> DR. BULL: I was just going to ask the question, in the context of
> question six about an ideal refractive error, how would you define
> that for a clinical trial with an entry criterion of minus 1? Would
> success be that you kept that patient at the minus 1, or that when
> they are 40 years old is the goal to have then at minus 1.5 so they
> can comfortably read? What does this mean in terms of trial design for
> what we have under discussion?
>
> DR. GATES: Who wants to take that?
>
> DR. WEST: I just don\'t think that there is any blanket statement that
> can be made for what is the ideal refractive error for all people.
> What is my ideal may not be what my best friend\'s might be if she is
> a mountain climber and never reads. So, it is very different and will
> depend upon what that child is destined to be as to what their
> refractive correction should end up being. I am very happy as a minus
> 1.5 and a minus 3. I do a lot of needlepoint so I would prefer to have
> my near eye a little bit nearer than my taller colleague.
>
> DR. BULL: I can\'t resist the urge to follow-up because I guess this
> gets to something that Dr. Gorman is aware of with pediatric
> interventions and things that say if you had been a child and your
> parents elected to have your myopia arrested so you never got to your
> minus 1.5 and your 3 that you are happy to have\--we are looking at an
> intervention that has long-term implications for a child and asking
> parents to make decisions for that child based on their concerns at a
> particular age. I guess, as you alluded to, we could end up with the
> situation where the child\'s ideal may not have been what the
> parent\'s ideal was. I feel a little bit compelled to make that point.
>
> DR. GORMAN: The comment that you make, I think most of us eventually
> become happy with who are, no matter what that is. But I think if you
> were going to ask\--I can\'t redesign the study and I can\'t redesign
> the agency, but I think if you wanted an outcome that I think everyone
> around the table would agree with as a parent of their child, if you
> could prevent them from having to put on glasses the first time, they
> would take that. But we are dealing with a group that, to identify
> them well, already have to have glasses on. So, I think if you are
> looking for the intervention that would be the ideal it would prevent
> them from having to wear glasses during their childhood. Then, when
> you get to be\--how old?\--65 when you are going to need your
> glasses\--
>
> DR. BULLIMORE: Forty-seven\--
>
> DR. GORMAN: Forty-seven when he needs his glasses, as the closet
> presbyope, then you can deal with them as adults deal with putting on
> glasses. I think that would be ideal but that is not the world we are
> presently living in. We are living in a world where I think you are
> going to have to define ideal as slowing the progression of their
> myopia and not have a number. It is going to be a slope issue.
>
> DR. GATES: Any other comments on number six? We will proceed to number
> seven, how much of a refractive change is considered an important
> change for an individual who would otherwise have the following
> refraction? We can just go down the list as such.
>
> DR. STEIDL: Well, I think you need a global concept, so the idea for
> example of doubling of the visual angle, to me, is a reasonable one. I
> think it was a 0.75 change that we said. I wouldn\'t come up with a
> different one for each of these, personally, but I am curious what
> other people think.
>
> DR. MILLER: I agree with that because I don\'t think it is something
> we can reasonably control. We are talking about a study where we are
> including kids where they just go along with their natural history
> versus, if they follow the tables, we shouldn\'t be getting very minus
> 7 or minus 12 in the whole study.
>
> DR. CHAMBERS: Can I try and rephrase this question? The idea of this
> question is you enroll whatever population you enroll and half your
> group, say, gets one intervention and the other half gets the other,
> and your control group ends up, say for (d) with minus 4. What would
> you want the treatment group to be to consider that a success? So, if
> the treatment is minus 3.75, or minus 3.25 and the control group was
> 4, if the matched control patient would have been 4 and you have now
> made them 3.25, did you help them?
>
> DR. BULLIMORE: What did you enroll them as?
>
> DR. CHAMBERS: The issue is not how they were enrolled\--
>
> DR. BULLIMORE: Well, it is\--
>
> DR. CHAMBERS: \--the control group is going to go through its natural
> history. Maybe it is a ten-year trial, maybe it is a one-year trial,
> this is looking at the endpoint. How much of a change? I guess in my
> mind I would have thought if you were going to be a minus 1, and we
> are trying to change you from being a minus 1, you might put up with
> something a little bit less than if you were going to be a minus 7.
> You probably wouldn\'t be as happy if you only changed 0.75 diopter.
> That was the way I was thinking of the question but, you know, the
> question is for you to answer.
>
> DR. BULLIMORE: I will take a stab at your question in a minute but if
> you enter the study as a minus 1 and you were destined to be a minus
> 4, then the expectations are very different than if you entered the
> study as a minus 3 destined to be a minus 4. So, you know, we could
> have all sorts of 6 X 6 tables and mark what the number would be in
> each, but I think from a practical point of view I am still coming
> down to, you know, 0.75 being the minimal effect that is meaningful.
> Clearly, what you are leading us towards is that for people with high
> degrees with myopia, you know, should we consider a larger number to
> be a meaningful change? Certainly, if you go down to the 7-12 diopter
> range, a minus 0.75 difference when you are a minus 10 isn\'t going to
> mean beans to your quality of life or anything.
>
> In that regard, for the high myopes, the rapidly progressive myopes,
> if you like, you might want to set the bar a little higher. But I
> think, given the entry criterion of a diopter, your control group is
> going to end up probably in the 3-5 range. What is meaningful? I
> don\'t know, a halving? What does that give us? I can\'t do the math.
>
> DR. CHAMBERS: The other part of the question, and the reason there are
> these different ranges is because, say, in the (a) group if you were
> destined to become a minus 1 you might argue you don\'t want to be
> moving from that. Based on what some of the people were saying earlier
> on, that is what you would like to continue to be on.
>
> DR. BULLIMORE: And based on our entry criteria of one diopter, you are
> not; you are not going to get any better. It is kind of moot for that
> group. I think we should concentrate our efforts, in terms of what we
> know about progression of myopia and the age range we are thinking
> about for these kids. Thinking about (c) and (d) here, people are
> going to end up in the 2 and 5 range is going to be the most fruitful.
> Really the ones at either end are either outside the purview of the
> kind of trials we have been discussing today, unless we go back and
> start to think about predicting myopia and treating it before it
> becomes manifest and if we want to consider the high myopes separately
> but, you know, the common or garden type of myopia that we have been
> discussing today is contained in the 2-5 diopter destination range.
> That is where most of these kids seem to end up. We got the
> percentages from the Framingham study which suggest that that is the
> bulk of the myopia, and of course I can\'t find it in my handout now.
> So, I think ultimately that is where it is easiest for us to come out
> with a number.
>
> DR. CHAMBERS: If you want to start there, but we are trying to think
> of a guidance that covers all the different ranges of different things
> that will include people where we will attempt to treat high myopia as
> well as those people where we will try to arrest progression very
> early on. Even if it is not the first thing that is studied, we are
> just trying to get as much information as we can from you at this
> point in time.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I think when I was reading the briefing packet I missed
> why there were two potential different outcome analyses presented by
> the sponsor. I think I now understand. Because I think there is an
> actual objective criteria that makes some sense of a different
> prescription, 0.75 or 0.5 diopters, but there is also another
> progression category of how many people progress to severe impairment
> of their life. I don\'t think they are independent. I thought they
> were independent before I got here this morning, but now I am
> convinced they are not independent. I don\'t think they should,
> therefore, be independent outcome variables. So, there needs to be
> some criteria linking that for people who don\'t progress very far,
> smaller numbers are okay; it shows an effect, but for people
> progressing a long distance, they can\'t progress as far as they would
> have. So, there needs to be a study of proportions of whether or not
> the same number of people get into the life-interfering level of
> myopia.
>
> DR. CHAMBERS: Right, and that is why this question was written for the
> individual.
>
> DR. GORMAN: Right, so for the individual there has to be a minimum
> criteria that their particular eyes have to do no less than 0.75
> diopters or less than 1 diopter for their eyes. Then, as you take them
> into their group of people, whatever group they fall into, not very
> fast progressors, progressors or rapid progressors, they need to be
> not progressing as a group as far as they would have been predicted
> to. So, for the individual at least a diopter or 0.75 diopter and
> then, as a group, not going as far as they would have been predicted
> to.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Just as a clarification, are you trying to separate these
> into groups of people who progress at different rates? Because I think
> what we have been hearing from Novartis is that their data at this
> point says that there is a certain average progression, 0.5 per year
> and maybe Asians might be faster and that you can predict, based on
> where they start, roughly where they are going to be in a few years.
> Because we don\'t know who they are going to be necessarily unless we
> are following them for a period of time ahead of the study, at what
> rate they are.
>
> DR. CHAMBERS: We don\'t know exactly\--I mean, the idea was to try and
> say we will have a control group for all these particular things and
> look where the control group tends to put people, and then look and
> see where the treatment intervention has taken that group. The idea is
> have we made a difference in that group? You can judge that either by
> means or you can judge it by percentages that have reached some
> particular criteria but we were trying to get a sense for an
> individual how much of a difference do we think we would want to have
> accomplished to have made a difference to them. Maybe that answer is
> 0.75 diopter; maybe it is 1 diopters, maybe it is 10 diopters. We are
> asking the question.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I think that although Novartis has proposed to study, and I
> think it is reasonable to study just the refractive change, all of us,
> as ophthalmologists and optometrists, would hope that if this drug did
> have an effect on refractive change there would also be a change in
> the proportion of people that then development complications of
> myopia, including myopic retinopathy and all those things.
>
> So, I think that you need to think about the person who is a 5 diopter
> myope versus a 9 diopter myope in two ways, one, in terms of their
> refraction and the practical implications of going with or without
> their refractive correction, in addition to considering the possible
> complications. So, an 8 diopter myope and a 12 diopter myope, neither
> would functionally read without their glasses because their working
> distance would be too short, but you would be better off as an 8
> diopter myope than a 12 diopter myope in terms of your chances of
> developing a Fuchs\' spot or a chordal neurovascular membrane. So, you
> are asking both questions, I guess.
>
> DR. CHAMBERS: Correct.
>
> DR. WEST For me, I think I can answer explicitly that it appears to
> be, if you look at the data from Vongphanet, in
> [Ophthalmology]{.underline}, 2002, that a 1.5 to 2 diopter change in
> the final level of ametropia is clinically significant in terms of
> what you end up with for correction of complications from high myopia
> when you are above a 5 diopter myope. But, practically speaking, for
> any of those you are not going to go around without your glasses.
> Then, I think that for people who are less than 5 diopters myopic,
> probably 05. to 0.75 is clinically significant for going without
> refractive correction because the risks of complications from myopia,
> sight-threatening complications, become far less.
>
> DR. BULLIMORE: Those are the numbers I have written down. I think if
> you look at the data both for retinal detachment and myopic
> retinopathy, if you are destined to be in the 5-7 bin there is a real
> benefit in being in the 3-5 bin. So, you might have to treat somebody
> for a long time and start early to keep them that way, but 2 diopters
> seems to be a tangible benefit in that group. But in the lower groups,
> 0.75 plus/minus 0.25 seems to make good sense. Keeping them out of the
> high range is the goal. If you want to go to the very high range, even
> 7-12 diopters, I think to make a meaningful difference you have to
> knock 4 diopters off it but those are an exceptional group of patients
> rather than particularly common.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: There was an important point about a co-primary endpoint
> made. Just to be clear, a co-primary endpoint makes a study very
> complicated. I think what the sponsor, in their slide 49, has proposed
> is an endpoint based on means. So, for a population treated versus a
> placebo group, having some change from baseline as a mean versus
> another possible endpoint, having a proportion of subjects achieving a
> certain amount of change in the placebo group and probably having a
> smaller proportion of patients change. Putting those two things
> together can be important. It can be relevant. It is done. It should
> be known by the committee that saying that these two things are linked
> and you have to win on both of these can be a daunting task.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: You are dealing with the schizophrenia of pediatricians.
> We have the desire to treat the individual, which was one part of the
> question, but we also have a public health role. If I couldn\'t
> guarantee that you would be able to walk around without your glasses
> but I could predict that your chances of retinal hemorrhage, tears or
> eventual blindness would go down by this treatment, both of those I
> would consider wins. I didn\'t mean to tie them together, except, as
> my colleague who spoke later, if you are in the low myopic group 0.75
> makes sense. If you are in the high myopic group moving down a couple
> of buckets makes sense. I think they presented it much more clearly
> than I did. But I am not sure if the drug has no effect at the lower
> diopters but has a great effect at the high diopters it wouldn\'t be a
> drug that wouldn\'t be pursued, you know, in terms of having a public
> health benefit rather than an individual person benefit.
>
> DR. GATES: Wiley?
>
> DR. CHAMBERS: I don\'t know if we have heard from everybody.
>
> DR. MILLER: No, I think that the primary outcome, the way it has been
> described by the sponsor, looking at the 2 diopters, the proportions
> in the two groups is reasonable, and that the data will be there to
> look at what happens in the higher group. It sure would be nice if it
> just plain cut off the higher end, but I don\'t think that that is
> necessary to prove. By having this discussion we have already decided
> that it is reasonable to do this in the groups that are not rapidly
> progressing. So, we should accept a difference between the groups with
> the lower myopias. So, I don\'t think we have to get into this
> discussion of the higher group and we will find out over time whether
> there is some benefit with retinal disease.
>
> DR. GATES: Would anyone else like to comment?
>
> DR. CHEW: I would agree with that. I think it would be very hard for
> us to think that we could demand an outcome that is sort of
> proportional, like a 25 percent change depending on where you are
> coming from. I think that is a very difficult endpoint to work from. I
> think it keeps it much cleaner, and we are starting with probably not
> quite as high myopes anyway to begin with and if you are going to
> demand more of that, I think that is very tough to do for a sponsor,
> for anyone to do. I think it would be unfair to give that sort of
> outcome. I think what is clinically significant, as we have discussed,
> is 0.75 diopter is meaningful. So, I think it is important to stick
> with that regardless where you came from.
>
> DR. CHAMBERS: I couldn\'t keep track because you were skipping around.
> Is that everybody?
>
> DR. FEMAN: I don\'t know if I officially commented during that session
> but I agree with what Dr. Chew just described. I think someone earlier
> talked about the practicality from an individual\'s perspective, that
> at a 0.75 diopter change you are going to go get yourself a new pair
> of glasses, no matter what. So, if you are stabilizing someone so that
> they don\'t have a 0.75 change, no matter where they are in the range
> between minus 1 and minus 7, you are going to prevent them from having
> to buy a new pair of glasses. So I think, just like Dr. Chew had
> indicated, it is appropriate.
>
> DR. GATES: Yes, Dr. Miller?
>
> DR. MILLER: I have one question. We have talked about our stable group
> definition, less than 0.5 a year and that progression is 0.5 diopter a
> year or 0.75 diopter a year. When we discussed it we talked about 0.5
> diopter a year but often we have gone into Dr. Joseph Miller\'s
> discussion of 0.75. I just wondered what we have decided as a group.
>
> DR. BULLIMORE: I have been working on the assumption that question
> seven refers to the duration of the study. So, I have been working on
> the assumption of at the end of the study or at the end of the
> intervention period, what is a meaningful difference, whether that is
> two years, three years, four years, but what would make a difference
> at the end of the study; how much difference between the treatment and
> the control groups would be meaningful to you as a patient and/or a
> clinician.
>
> DR. MILLER: Right, as 0.5 diopter or 0.75 diopter per year or the 2
> diopters proportion\--I am confused now. Wiley?
>
> DR. GATES: Wiley, would you clarify? Dr. Miller has a question over
> the time span.
>
> DR. CHAMBERS: The assumption in question seven was at the end of the
> trial, how much of a change you were basically going to effect from
> the beginning of the trial to the end of the trial, not per year;
> total amount of change.
>
> DR. GATES: Everybody had time to express their opinion on question
> seven. We will move on to number eight.
>
> DR. CHAMBERS: What I have heard has been ranges between 0.75 diopter
> and 2 diopters. That is what I heard as people went through.
>
> DR. BULLIMORE: Are we going to go back and vote on these one by one?
>
> DR. CHAMBERS: No.
>
> DR. BULLIMORE: Okay, well, let me see if I can get some consensus
> then. For (a) through (f), I have written down 0.5 diopter, 0.75,
> 0.75, 0.75, 2 and 4, 4 being for the 7-12 group.
>
> DR. GATES: Any other comments, or would anyone like to propose any
> other criteria for the categories?
>
> DR. CHAMBERS: As I said, we are not looking for definitive votes or
> answers. We are looking for ranges. This is a starting point to try to
> develop a guidance.
>
> DR. GATES: So, we will move on to number eight, what is the minimum
> amount of change that would be considered a pharmacological success in
> slowing progression? Why don\'t we start over on the left-hand side of
> the room? Dr. Plott?
>
> DR. PLOTT: Just listening to what I have heard here\--I am not the
> expert, but what I hear is that 0.75 of a change is important and that
> is what I would stay with during the course of a study.
>
> DR. CHAMBERS: This particular question is rate. Whereas the last
> question was the total amount, this question is rate.
>
> DR. GATES: Rate.
>
> DR. WEST: Can you go on to the next and then come back to me?
>
> DR. CHAMBERS: That is the chairman\'s prerogative and he is welcome to
> do it whichever way, as well as if you think this is not the way to be
> studying things. I mean, remember we wrote these questions ahead of
> time, trying to make sure we covered different bases. If you think
> particular questions are not relevant, tell us so.
>
> DR. WEST: No, what I was just trying to figure out was the rate
> because we have really been thinking about the endpoint over time. If
> someone is looking at the data, that there is a different rate for
> different ages and you would need to cut your rate by a different
> amount at different ages to end up having a clinically significant
> outcome. I was just trying to figure out what that was.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I think this question is unanswerable in our present
> understanding of the agent. If the agent works by stopping the
> progression for 18 months and then it goes back to its previous rate,
> no matter what you do, is one answer. If it is equally effective, no
> matter what the progression rate\--I mean, this agent may be very
> effective in the 3-6 year old range, 6-9 year old range, or it may
> have a fixed rate reduction so it always reduces it by 10 percent of
> whatever its growth rate is. Since we don\'t know how the agent works,
> I am not sure that the rate becomes a meaningful question as much as
> the outcome. If it is a steady state effect over the course of
> therapy, then this is a meaningful question but if it is not a steady
> state effect over the progression of the disease, then this question
> has little meaning except in terms of the endpoint of how much does it
> slow down the progression.
>
> Because we don\'t know how this agent or other agents that may come
> down the pike are going to affect the progression, I want to use the
> analogy of when HMOs came alon there was a huge cost savings for one
> year and then the rate of increase progressed from then equally. So,
> for one year we saved all that money and from then it just progressed
> at the regular rate. If a drug works like this, then there will be one
> year where there will be zero growth. And, it may be growth dependent.
> If the eye is growing in axial length it may only slow that rate of
> growth by a certain amount. I am not sure we know enough about the
> agent to answer this question.
>
> DR. BULLIMORE: Dr. Gorman is speaking as if he has read the myopia
> clinical trial literature very carefully because there is an emerging
> body of evidence that suggests that for certain therapies you get a
> lot of effect in the first year and then the two groups basically
> follow a parallel course beyond that. So, I would share Dr. Gorman\'s
> hesitation about defining what is a successful rate when that slowing
> may vary at different times of the study. Of course, at the risk of
> misquoting Dr. Gwiazda\'s COMET trial, I think they observed a
> relatively large effect in the first year of the study and smaller
> effects in years two and three. I think we see that in the atropine
> data as well and maybe in some other trials too. So, you know, if the
> FDA wants a number, then, I don\'t know\--an average of 0.25 diopter
> over the duration of the trial.
>
> Certainly in light of what has been discussed here, I think it is
> important to have a period of time greater than a year. It would be
> ignoring recent studies to do a one-year trial and feel that was
> sufficient. But two to three years seems to be the minimum, and a rate
> of change, if you want a number, 0.25 diopter per year but I would be
> cautious about holding someone to that number when the effect may vary
> from year to year.
>
> Corneal curvature, we are not expecting to change given the current
> ranges of agents that have been tried and tested. So, I don\'t regard
> that answer relevant. So, 0.25 diopter, 0.1 millimeter axial length
> but with a caveat that this might vary over the course of the trial,
> the effectiveness of the agent may vary over the course of the trial.
>
> DR. GATES: Any other proposed baselines? Dr. Steidl?
>
> DR. STEIDL: You could look at this from the point of view of what does
> the patient want, patient satisfaction, quality of life. That would be
> very difficult to assess but, from my point of view, I am still quite
> concerned about pathologic changes. So, you arrive at a number. Like
> you said, when you hit minus 5 your likelihood of developing
> problematic retinopathy increases. Then to come up with an answer for
> this, I would do calculations based on that. If you are minus 4, small
> increases to that number would be significant. If you are minus 1, you
> know, your rate might change depending upon the time when you are
> looking and all of that, but I would use that as the endpoint and
> calculate everything from that since that is the one absolute concern
> that could lead to severe vision loss.
>
> DR. MILLER: That is very interesting to me but my concern with that is
> you might decide that the drug was a failure but there might have been
> a role if you had started the treatment earlier. So, it might make
> sense to look, as has been suggested, over a longer period\--because
> we don\'t know much about the rate of this, to look at it over a
> longer period of time and have a manageable number like 2 because we
> know in the normal changes it is 0.5 diopter a year. So, if over 30
> months we are looking at some people who have come up by a 2 diopter
> change, then for people who have followed the normal curve we have
> gone long enough to know that something different has happened.
>
> I am very interested in axial length measurements getting measured, to
> know that information as a pediatric ophthalmologist, but it is really
> refractive error as the endpoint that is important because with kids
> you can get some error and you get more of a numerical change with
> refractive error for the millimeter change. So, I would stick mostly
> to refractive error and secondarily measure axial length in these
> things. That is why I haven\'t talked about it that much.
>
> DR. GATES: I concur. I am very interested in the refractive error as
> opposed to the axial length. I am interested in that data
> retrospectively to see where it goes, but I am more interested
> prospectively in looking at refractive error.
>
> DR. FEMAN: I agree with what you have just discussed. Essentially, the
> study is designed to be measuring the change in refractive error and
> we have already discussed these levels. These other features, axial
> length, cornea etc., are just things to be measured while we are doing
> it.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I don\'t have anything more to add.
>
> DR. GATES: Any other comment on number eight? Dr. Miller?
>
> DR. MILLER: You could say that the study drug is a roaring success if
> you don\'t get any minus 5 or worse myopes and it is a failure if you
> do, in a sort of simplistic way, if you want to look at the pathologic
> myopia. Anyway, I think we have covered this.
>
> DR. GATES: All right, we will change cues here and go to number nine
> and start off with Dr. Steidl. What are clinically relevant,
> acceptable endpoints of myopia-induced ocular disease? We have talked
> a little bit about the refractive error and now we will talk a little
> bit about the disease.
>
> DR. STEIDL: Relevant and acceptable I guess are different. We
> wouldn\'t accept retinal detachment. All of these things are relevant
> and I guess there are many ways of looking at this question but the
> most important thing I think to follow for is development of retinal
> tears, glaucoma that couldn\'t be otherwise explained and development
> of retinopathy. Lattice degeneration is common and that is not I think
> a particular issue although you want to know that it is there. Retinal
> holes generally, depending upon who you read, can be followed but,
> again, you would want to know they are there. Retinal detachment is
> quite a catastrophic event so, again, you would want to know about
> that but that wouldn\'t be an acceptable endpoint. So, I guess it
> depends on how you define it.
>
> DR. CHAMBERS: Yes, say in a trial we were not going to follow for the
> refractive change. Say we were just going to look at the two groups
> and say, okey, the endpoint is going to be retinal detachments. If we
> get less retinal detachments in the treatment group than in the
> control group, is that something we should approve a product based on?
>
> DR. FEMAN: I have a problem with the discussion going on because the
> literature at the present time does not show that these are cause and
> effect relationships to myopia. They are coincidental to the disorder
> but just because a person is a myopic is not what causes them to
> develop the retinal tear. Retinal tears develop in people that are
> myopic. These are associations but not causally related. So, that is a
> different approach than saying this is a treatment done to prevent a
> retinal disorder of some sort. Unless someone else is aware of
> literature that I am not aware of. Emily?
>
> DR. CHEW: Well, my concern is that, you know, if we are looking at
> these as endpoints you are going to have a long, long-term study.
> These things don\'t happen in children. Retinal detachments are in
> much older people so you are not going to be able to look at this
> until years, and years, and years, decades down the road. We already
> have very good data that suggests that retinal detachment is
> associated with increasing myopia. The risk more than doubles if you
> are even 1-3. So, I think it is going to be very hard to incorporate
> this in a clinical trial that you are going to demand of a myopia
> study. That is my personal view. These obviously are very important
> clinical features that we are hoping to prevent, but there is no way
> you are going to be able to design a trial that is only that long to
> look at it.
>
> I think Steve is right, there are some associations, like lattice
> degeneration, that may not be just myopia. It is fairly common and
> people don\'t treat lattice degeneration or asymptomatic holes. Those
> are not important unless they become symptomatic with retinal tears.
> So, these are difficult endpoints that I would not put in a trial for
> myopia treatment.
>
> DR. CHAMBERS: We are basically looking for different options. We are
> trying to give sponsors different choices and ways to do the trials.
> Whether you agree that is the most efficient or the best way is one
> story, but if you were to design a clinical trial that said I am going
> to treat one group with one particular agent and have a control group
> there and you found less retinal detachments in your group, would you
> say that was a legitimate endpoint to use to approve the product?
> Clearly, we have put in a number of different things.
>
> Yes, we recognize that lattice is far less serious than having a
> retinal detachment. If I had to guess about how you would answer the
> question before we started, I would have said retinal detachment was
> fairly straightforward, you are all going to say if we prevent retinal
> detachment, that is a good thing. I am not so clear about a bunch of
> the other things that are on here. So, that is why they were put into
> this question. The assumption is not whether the trial can be done or
> not. It is, if we were to try and use anatomical endpoints, which ones
> do you think would be appropriate and which ones would not be
> appropriate to use as an endpoint, assuming the trial is 20 years
> long.
>
> DR. BULLIMORE: So, you want us to enter into your fantasy world right
> now?
>
> \[Laughter\]
>
> With all respect, it just seems, you know, a waste of everybody\'s
> time to be discussing even the concept. I mean, just thinking about
> the duration of the study and the sample size, retinal detachments
> even in a myopic population, have something like 0.6 percent per year
> event rate. I don\'t have enough life expectancy to do this study.
>
> DR. BULL: Just as a point of clarification, I think the intent was not
> just to think in the box of the example provided by Novartis, but if
> you were hypothetically, as Wiley pointed out, to conceive of a study
> design that would look at an anatomic type of endpoint, does that have
> any relevancy here? From what I am hearing, I think it is certainly
> reasonable that these kinds of endpoints would not be ones that you
> would reasonably see in the pediatric age group for a study that would
> have the kind of duration that one would look at to try to get a drug
> on the market in our lifetime; that to try to see whether or not the
> children enrolled would develop these is conceivably so long that it
> would not occur within what would be a two to three-year study frame,
> if that is deemed to be an acceptable time frame for the study. But I
> think it is raising the question, trying to look at potential models
> of looking at endpoints for the study and to get your comments on
> that.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Briefly, you said we could say if we didn\'t think it was
> a relevant question and, in a sense, I would say that that is the case
> here just in the case, as you were saying, of a reasonable study of
> appropriate duration. I would say (a) through (e)\--I agree with what
> Dr. Feman says, that, in fact, it is pretty hard to connect those to
> myopia from the start. What is relevant is development of
> myopia-related retinopathy and you would have an enormously long study
> for that. So, I don\'t think it is really relevant as a question.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I was reacquainted with the word earlier when someone used
> it, recidivism. If some of these rare events occur in pediatrics and
> they have a repeatability that is predictable, such as retinal tears,
> and if you have one, will you have another? If this drug was shown to
> prevent the repeating or the recidivism rate, reduce the recidivism
> rate, I could see that as being a useful piece of information but
> certainly not for the indication presently sought by the sponsor.
>
> DR. GATES: I would love to know this information but I think, you
> know, the time over which it would be attainable would be
> insurmountable. Has everybody had a chance to make a comment that
> would like to on number nine?
>
> Let\'s go on to number ten. Which method or combination of methods do
> you consider the most reliable and reproducible for the assessment for
> measuring myopia in children? Dr. Steidl, do you want to begin again?
>
> DR. STEIDL: I see the argument for the automated refraction and
> perhaps, just in practical terms, that is the best way to go. If you
> could have certified examiners who could fly to locations for
> difficult cases, for example, if you did serial axial length measures
> and got really erratic readings because of child compliance or other
> reasons, that might be a nice backup. When I was reading this, I
> didn\'t initially think that auto refraction would be reasonable but I
> think that it might possibly be now. I don\'t have anything to add
> with regard to axial length measurements in kids because I have never
> tried it and I don\'t know anything about it.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: Clinically the gold standard that we use all the time is a
> physician cycloplegic refraction but I think for the purposes of the
> study automated refraction will be the most practical. My question is
> which cycloplegic agent will be used. It should by Mydriacyl; it
> should be Cyclogyl one percent, in my opinion. In this age group even
> consideration should be given for an atropine refraction, but that is
> something that should be talked about because those numbers can be
> very different.
>
> I don\'t see axial length on there\--yes, I do axial lengths in
> children this age before cataract surgery without much difficulty. So,
> I think you will have an occasional child you can\'t do it with but it
> is doable.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I defer to my colleagues who do this on a daily basis.
>
> DR. GATES: I am agreeable to cycloplegic auto refraction if the other
> colleagues that work with children on a regular basis feel that is
> valid. I would concur with that.
>
> DR. FEMAN: My only question is that I don\'t see cycloplegic auto
> refraction on that list. Is that what you mean by number (a)?
>
> DR. GATES: On our papers it is (d).
>
> DR. FEMAN: Okay, cycloplegic auto refracted spherical
> equivalent\--somebody had debated whether or not a spherical
> equivalent is an appropriate term. I think (a) as a cycloplegic
> automated refraction ought to be the option. I think that (a) should
> not be just automated refraction but cycloplegic automated refraction.
>
> DR. CHAMBERS: That is why we have (e) there.
>
> DR. FEMAN: Well, that is (e).
>
> DR. MILLER: I agree with Dr. Feman. I agree.
>
> DR. CHEW: I think the cycloplegic is important also in terms of asking
> if there are going to be adverse effects you are going to see, and I
> think important to mask for the investigator, the examiner, to really
> try and cut down on bias as much as possible.
>
> DR. BULLIMORE: Yes, cycloplegic auto refraction. I think atropine is a
> little cruel and unusual even for this kind of study. Personally, I am
> a big Mydriacyl fan but I can live with Cyclogyl. I defer to Dr.
> Miller.
>
> As far as axial length measurement, ultrasound is good and doable. I
> don\'t have an interest in the company but the Zeiss IOL Master is
> excellent in myopia studies. It is objective; it is quick; it is
> non-contact and its repeatability is exquisite. It is really very,
> very repeatable. But, obviously, requiring a sponsor to use a specific
> instrument is probably inappropriate but just to draw people\'s
> awareness to the fact that there are alternatives to ultrasound out
> there that may fit the bill very well.
>
> DR. GORDONSON: Cycloplegic auto refraction is the best if you are only
> looking for change. As long as you don\'t prescribe it, it is fine.
>
> DR. WEST: Automated refraction without cycloplegia is worthless.
> Cycloplegic refraction by an observer is not reproducible. Axial
> length is a measure only of axial length and not of myopia without
> information about the contribution of the refracting elements of the
> eye. So, that is unacceptable as a primary outcome. Cycloplegic
> automated refraction is the most reproducible but it has to have a
> sufficient cycloplegic agent for all colors of eyes, realizing that
> blue eyes in general will have a larger effect from tropicamide or
> cyclopentolate than dark irises will. So, I would vote (e), other,
> cycloplegic automated refraction, not spherical equivalent because of
> previously stated loss of information.
>
> DR. PLOTT: I defer to the experts.
>
> DR. GATES: Any discussion? We will go on to number 11, starting on the
> left-hand side. \"High\" myopia has been attributed to a diminution in
> an individual\'s quality of life. How is quality of life most
> appropriately assessed in these clinical trials? Dr. Plott, do you
> want to begin?
>
> DR. PLOTT: I have just a little bit of experience with quality of life
> trials, enough to know that they are very highly variable instruments
> and they need to be validated. This particular population presents an
> unusual challenge because of the age. So, to use a validated
> instrument would seem to be very difficult without validation. There
> is something to be said, just for the common sense quality of life and
> being able to see better. That is about all.
>
> DR. WEST: I don\'t know of a way to assess quality of life in an 8
> year old with myopia.
>
> DR. GORDONSON: High myopia is going to be found later. These kids may
> be projected to have high myopia but at the ages at which they are
> going to be studied\--and kids always say everything is okay\--\"How
> are you doing in school?\" \"Things are okay\"\--even though a report
> card says otherwise.
>
> \[Laughter\]
>
> So, I don\'t know how this question applies. Even adults, if you have
> to ask them do you want to go through this business or accept the way
> you are, I don\'t know what answer you would get.
>
> DR. BULLIMORE: As Novartis and the experts suggested, there are things
> like the RSVP and the RECQ that have been developed to assess quality
> of life as a function of refractive error and refractive correction,
> but I am not aware of those being used in kids. I guess there could be
> an instrument developed. I think issues of dependency on the
> refractive correction, quality of vision without their correction, all
> those kind of things are the issues that I think should be on there,
> but I am not about to go develop an instrument to do it. I think that
> is up to the sponsor to do, but one would like to see the appropriate
> validation done before it is used in a trial of this nature.
>
> DR. CHEW: I would agree with Mark. I think the other issue you have to
> address is the adverse effect of treatment. That has to be in the
> quality of life questionnaire as well, what sort of tolls does it
> take, and it would have to be addressed to the family, you know,
> parents as well rather than just the child.
>
> DR. FEMAN: Well, quality of life is something that is very important
> for all of us. The National Eye Institute has already
> established\--correct me if I am wrong; Dr. Chew works there once in a
> while so she would know in more detail\--
>
> \[Laughter\]
>
> \--but they have already established a superb quality of life
> technique for evaluating such changes in adults, particularly when you
> are studying macular diseases and things like that. There is a group I
> guess in Philadelphia that does econometric planning based on these
> quality of life statements so one can really use this to talk about
> dollars and things like that. But I don\'t know that anyone has
> extrapolated this to the pediatric population. Wouldn\'t this be a
> lovely population for someone at the Eye Institute or elsewhere to try
> to develop a quality of life system?
>
> DR. CHEW: That takes a lot of resources and a lot of time. So, it is
> not so simple. I think that the NEI FQ took several years of just
> field testing and focus groups. It took almost five years before it
> was developed. So, unless the sponsor is willing to wait for five
> years, I don\'t think you want to do that. But that is a challenge.
>
> DR. GATES: I would concur that delves very deeply into social sciences
> beyond my scope. Dr. Gorman, I will pass to you.
>
> DR. GORMAN: I defer to my colleague on the right. I wrestled with this
> question more than almost any of the other questions on the list,
> especially since the reality is that assuming the drug or other drugs
> are effective and they don\'t arrest progression, they just slow
> progression, the quality of life for both of these groups is going to
> deteriorate. Pharmaceutical companies and myself are always looking
> for things that improve quality of life, but in this particular case,
> if it is a sensitive measure and it actually works, the quality of
> life will be deteriorating but just not as much as in the other group.
> So, it is going to be a very difficult thing for the marketing force
> to go out with to say, \"oh, if you use this you\'ll only be half as
> unhappy as if you don\'t use this.\"
>
> \[Laughter\]
>
> So, it posed some difficulties for me. I think there are global
> indexes of the quality of your life that are available in pediatrics
> that are not very sight sensitive, but they are there and they have
> been validated, but they are global and I am not sure how many of the
> questions are going to be specific enough that the visual acuity is
> going to factor into it. But I would continue to look at participation
> in sports, cessation of activities that people used to do. Adults
> generally find that they need glasses when they stop reading and start
> watching television at night and then they realize that perhaps
> something is wrong with their eyes; they can\'t read anymore in the
> dark or maybe they go to restaurants and they can\'t read the menu.
> But I think one of the things I would be looking for, for my personal
> thing, is activities that were ceased and see if the treatment group
> ceases fewer activities than the non-treatment group.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I would be particularly interested in reading and near
> activities. I don\'t know of any scale for that but, you know, how
> long they spend doing the Game Boy or something. I am afraid it is
> going to affect some level of near work, from what I have heard. I do
> know some generalized scales on quality of life in kids in the
> diabetic population. I have seen some scales used even for children
> who don\'t write yet, looking at pictures\--\"are you more like the
> child on this side or that side\" in the book. So, there are measures
> out there but it is not something we have used in ophthalmology at
> all. It might be adaptable.
>
> DR. STEIDL: I think that quality of life is probably the most
> important issue, as is true of virtually everything that we do, but it
> is commonly not measured or measured well. This would be no exception,
> although I am not sure that it is measurable. So, I would be
> skeptical. Validating something that would be a reliable instrument
> might be out of the scope of what is possible, as Dr. Chew said. So, I
> don\'t know, I think it is important but I am not sure that it could
> be done, but you might run some pilot studies looking into the
> possibility of seeing how certain instruments or at least modified
> instruments could work.
>
> I am kind of concerned though about other things, and I think that
> they have to be followed. I know we are just generalizing here, but
> would medication affect growth? Would it affect psychology? Would it
> affect irritability? There are many other things that I think would
> need to be assessed that could come into the purview of quality of
> life but I don\'t think they are the kind of things you are going to
> ask a child. They may have to be objectively measured in some way.
>
> DR. GATES: Dr. Miller, do you have another comment?
>
> DR. MILLER: There probably are attention span indices that are pretty
> objective, if you were talking about reading scores and attention
> span\--I had a psychology background in college but it was a long time
> ago.
>
> DR. GATES: Dr. Feman?
>
> DR. FEMAN: Yes, just another comment because someone commented and I
> don\'t know if it was picked up at the microphone earlier, if we are
> talking about quality of life evaluations in children in this type of
> a study, we have to incorporate quality of life evaluations in the
> family because this child is not going to be putting the ointment or
> drops in their own eyes. So, one needs to extend this to not just the
> child but the family involved.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I am sorry, I thought the question was quality of life of
> high myopia which was the outcome, and I think the conversation is
> getting on to quality of life during treatment and I was looking for
> direction on which one we are being asked to discuss.
>
> DR. CHAMBERS: As you have probably figured out, we are interested in
> both aspects.
>
> DR. GATES: Well, thank you, all. We are going to take a ten-minute
> break now and we are going to convene promptly and finish the
> questions after that. Thank you.
>
> \[Brief recess\]
>
> DR. GATES: Thank you, we will begin, now that we are back in session,
> with question 12. How frequently should assessments be made? We will
> start with Dr. Miller, on my right, and we will go down toward my left
> and end with Dr. Steidl.
>
> DR. MILLER: I would suggest that assessments be made every six months.
> Then, I like the idea of the 30-month endpoint for the study, but I do
> think that for the rebound effect I would favor a year out. But I also
> think that right after the start of treatment an assessment within the
> first month, and then you could also check the vision with that new
> pair of glasses as kind of a double check on things too, but also
> check compliance and all the other basic study things. You want to
> make sure they are doing the study and you have connected them. But in
> terms of measurement of change, I would probably recommend
> cyclopleging them every six months and doing an auto refraction.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I think efficacy measures every six months is very
> reasonable. I think safety measures, every month for the first year,
> to be combined with dispensing of the medication and, therefore,
> measuring compliance because I think compliance in a twice a day drug
> over three years, with no\--how shall I put this?\--no hope of getting
> rid of glasses that you already have may become a major issue for the
> completion of the study. So, efficacy every six months; safety every
> month for the first year, combined with dispensing the drug and
> compliance measures.
>
> DR. GATES: I am comfortable with the assessments being made every six
> months. Dr. Feman?
>
> DR. FEMAN: I agree with what you have already discussed. I think Dr.
> Gorman raised a very important point though about having the family
> and the child return every month for safety measures and also to
> verify compliance during the introduction to the study. Whether that
> is for the six months of the first year I don\'t know but it needs to
> be done like that to be sure it is being done.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I would agree that the six-month visits for endpoint
> measurement is good but I question the monthly. As a clinical
> trialist, that is not easy, to have someone come back on a monthly
> basis. There could be telephone calls. It also depends on what adverse
> effects you are talking about as well. That also leads into the issue
> of rebound as well and how often would you do that afterwards. I think
> that has to depend. Some of the data they already have perhaps can
> help with that. I think it is hard to come up with hard and fast
> rules, but every six months at least for the endpoint and then,
> depending on what adverse effects you have, you can tailor that.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I think outcome measures every six months is more than
> enough. I could even be persuaded to go annually since we are
> cyclopleging and looking at something that seems to be progressing
> relatively slowly. As far as safety measures, obviously you might want
> to front-load your schedule a little bit and have a one-month visit
> but maybe six-monthly visits thereafter for safety issues. Obviously,
> compliance is going to be so important that I expect any
> self-respecting sponsor would work pretty hard at that and do whatever
> it takes, with people calling up and diaries and give them a video,
> showing them putting a drop in every morning\--I don\'t know.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: I think six months is a good idea, but certainly for
> compliance it probably will depend on experience\--judge how much
> fluid is left or ointment is left and being on the phone, and all
> that, but I think six months is very long to go unless you do
> something about compliance, whether it is one month or two months, or
> if you learn how compliant they will be as time goes by.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I too am comfortable with the every six months assessment.
> As a mother of two, I think that compliance is going to be a big
> issue. Even for something that hurts my child, like an earache or sore
> throat, it is difficult to comply with ten days of twice a day
> treatment, let alone three years or years and years in the very end.
> So, I think if there is a dose meter or if the sponsor\'s medication
> were to be in a liquid gel that could be sensitive to a tilt meter,
> that might be good, or perhaps weighing the residuals that come back
> to see how much, in fact, was used. It wouldn\'t negate against
> dumping of the medication to feign compliance. One could also survey
> not only the care giver but also the child separately. For instance
> with patching, when parents come back and say that they have been
> patching but when I put the patch on and the child asks, \"what\'s
> that?\" I know the compliance has not been\--
>
> \[Laughter\]
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: Probably the visit schedules are going to be driven by the
> need to get a new tube of medication and, you know, look at compliance
> from a practical standpoint and the evaluations only to the experts.
>
> DR. BULLIMORE: I am perfectly comfortable with just measuring one eye
> and cyclopleging that every outcome measure visit. How do other people
> feel about that, or do you want measures on both eyes?
>
> DR. FEMAN: Are you planning to test the drug in one eye of the child
> or both eyes of the child?
>
> DR. BULLIMORE: Well, there is a rule of diminishing return when, you
> know, you try and analyze data from two eyes. Certainly, if you are
> worried about respondent burden, dilating one eye in a patient to get
> an outcome measure is less of a burden from the point of view of the
> rest of their day than dilating both of their eyes. So, assuming the
> effect is going to be correlated in the two eyes, personally, I would
> seriously consider just doing the outcome measures on one eye and
> doing the cycloplegic auto refractions on one eye, whatever we thought
> the schedule was appropriate.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I disagree because one of the things in children that is
> very important is keeping the balance set between the two eyes so that
> you don\'t have a preference for one eye over the other. So, if one
> eye is changing\--you want the eyes to be the best balance possible.
> It mostly applies to the younger kids. In most kids you don\'t notice
> any change in their behavior with Cyclogyl in terms of going back to
> school. I just say you can\'t take a test today. But within three
> hours they are fine. The pupil is big for a long time. So, I would
> advocate checking both to keep the glasses with the same level of
> currency if you are going to change them.
>
> DR. BULLIMORE: Yes, I am assuming, and this might be wrong, that one
> might be prescribing glasses for the child independent of the outcome
> measure. For example, in the COMET trial there was a patient care
> team, I believe, that took care of the glasses and then there was a
> master examiner who did the cycloplegic auto refraction. Again, Dr.
> Gwiazda, I apologize if I got that a bit wrong. But that is not
> uncommon in trials of this kind. Obviously, there is a concern for the
> ongoing care of the child and they are going to get the usual standard
> of care in terms of their refractive needs, but in terms of
> cyclopleging an eye every six months to get an outcome measure, if
> there is no, or limited, statistical benefit of taking those measures
> on both eyes, then it can minimize the respondent burden by just doing
> one eye.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I think that there would need to be very strict guidelines
> as to spectacle prescription and on what one was basing it because
> that would be a potential confounding variable. If you were
> under-minusing that may accentuate any treatment effect of the
> proposed medication. So, if you decided that you would only do one eye
> each six months, you would have to have times when you changed
> spectacles either for loss, breakage or something like that. So, you
> would need the data from both eyes in order to give a balanced
> refraction.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: I think that is an extremely interesting issue, the idea
> of doing one eye. I would defer to someone who knows more about
> statistics of clinical trials, but it is intriguing. I would suspect
> the epidemiologists that I work with would want both eyes.
>
> I think the every six-month exam would be okay. You would have to have
> separate safety and compliance exams or phone calls. The alternative
> would be front-loading it so that you do it all in exams, maybe one
> month, six months, 12, like that.
>
> DR. GATES: Any other discussion? Well, let\'s go on to number 13.
> Trials should be of adequate duration to determine whether a therapy
> slows myopic progression, whether the effect is permanent as opposed
> to shifting the curve to the right, and whether there is a rebound
> effect after discontinuation. Assuming a best-case scenario where the
> drug product halts the progression of myopia, what would be the
> minimum? I would like to start with Dr. Miller again, if I may.
>
> DR. MILLER: I think that the 30-month duration proposed by the sponsor
> is really quite reasonable. My preference though would be for doubling
> the follow-up interval after treatment and then having some sort of
> monitoring for a longer period, but to have data presented on up to a
> year after treatment to understand the drug.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I also like the 30-month duration. If the treatment effect
> changes the slope by half it will give an outcome measure that we, I
> think, agreed would be both clinically and statistically significant.
>
> The follow-up after treatment in the active part of the study, I think
> six months to a year is reasonable because of the concern about
> rebound and, more than rebound, determining what the new slope of the
> line would be in terms of the progression of the myopia.
>
> I understand the difficulty of this and I certainly wouldn\'t make
> this a condition of approval of the drug, but I think there needs to
> be an endpoint that is somewhere further down the line to see what the
> final number is, whether it is what they predicted. If the lines
> diverge during the treatment and don\'t converge during the one-year
> follow-up, is the outcome different at 16 years of age? In other
> words, did you do anything at the final endpoint, if 16 is the point
> at which juvenile myopia stops progressing?
>
> DR. GATES: I would like to echo that the 30-month period is very
> doable and I think that is valid; also, with the 12-month follow-up
> rather than the six-month. Dr. Feman?
>
> DR. FEMAN: I agree with what Dr. Gates just said.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I think 30 months is reasonable. I don\'t know how ethical
> it is, I have been told it is not ethical to re-randomize these
> patients and have half of them stay on the drug and see what happens
> if you continue for another year-plus, compared to those who don\'t
> have the drug and see what happens with the rebound effect; whether
> the slope is different. If you kept them on, is there more suppression
> of the myopia? I think that 30 months seems reasonable but you may
> need longer than that and I think that may be something you might
> consider doing.
>
> DR. BULLIMORE: I will echo those sentiments. You know, we saw one
> study design presented and for the effect size 30 months seems
> reasonable, but I am sure a different sponsor or the same sponsor may
> come back with a different design, different sample size, different
> criteria. Six months or 12 months for the washout follow-up.
>
> I like the idea that Dr. Chew proposed for randomizing the treatment
> group to continuation or cessation of the treatment. Again, using the
> parameters presented by the sponsor today, I think that we should have
> a bucket-load of subjects available. The sample size can be driven by
> the safety aspects. If we are looking at long-term effectiveness of
> the drug we should be able to randomize the subjects once again and
> get some meaningful information. Now, whether that is handled in a
> pre-approval situation or as part of a Phase IV study, I don\'t know,
> but there is certainly some wriggle room around here.
>
> DR. GORDONSON: I think the 30 months is fine, and follow-up treatment,
> six months, and if there is an abrupt change we would probably hear
> from the patient anyway, so I think those are two good numbers.
>
> DR. GATES: Dr. West?
>
> DR. WEST: I agree with Dr. Gordonson.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: I will take a different point of view. Speaking generally
> maybe not just for this drug but other drugs that are studied in this
> indication, the duration of the trial should reflect the type of
> outcome that is expected.
>
> On sponsor\'s slide number 51, they anticipated a 50 percent effect.
> Let\'s say that that effect was, you know, a 75 percent effect, I
> think a clinical trial could be done of a shorter duration than 30
> months, or whatever the duration should be would be driven by the
> expected difference in the power of the clinical study to detect
> differences between active and controls. So, if there was a
> significant benefit, or let\'s say that we came across a product that
> simply halted the progression of the condition, then that might be
> something that we want to take to the market more quickly because the
> risk/benefit favored the product so strongly. So, thinking broadly, I
> think it has to be driven by the anticipated differences and could be
> shorter depending on what is anticipated.
>
> Where that comes from though is from good Phase II clinical trials,
> dose-finding trials where there are statistical trends that are
> developed on different doses and there are observations about what
> might be expected over a certain period of time or in a certain
> population with a certain concentration. So, I think it can be
> calculated not blindly but with the help of those Phase II clinical
> trials.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: I am equally interested I think in what happens when you
> stop the drug as to what is happening when you are giving the drug.
> So, I might differ from a few of the folks here. I understand the
> issues of cost and time. If you had six-month follow-up it might be
> one data point and it is hard to know exactly what that means unless
> it was dramatic. I might even be willing to hedge on the 30 months
> just to get a little bit more time on the other side. So, I would
> think you would probably want to follow for at least a year,
> preferably for me maybe longer, but I don\'t know what is feasible.
> But, you know, the 30 months would be adequate, as far as I am
> concerned, for the primary trial.
>
> DR. GATES: Any more discussion? For question 14 I would like to begin
> with Dr. West. I will read the question and we will come back toward
> my right. Refractive errors prior to age 7-9 years old may cause or
> correct amblyopia. Individuals ultimately developing high degrees of
> myopia frequently demonstrate refractive errors prior to ages 7-9
> years. Should children who are still at risk for developing amblyopia
> be studied, or should studies be limited to older children?
>
> DR. WEST: I think it is fine to include children who may be visually
> immature still, and those may be children that are less than 6 or 7 or
> it may even be children who are less than 10-15. We don\'t know when
> children become visually mature yet. The old dogma is that it is at 6
> years of age but, in fact, it is probably older than that and it
> probably varies from individual to individual. So, I think as long as
> the child receives the treatment in both eyes it is fine to treat
> children who are not yet visually mature. But I would be against a
> study that was designed where each child acted as their internal
> control for, if there was a treatment effect, it would have the
> potential to cause emmetropia, although the amount of effect that has
> been anticipated would not be likely to cause anisometropia that would
> cause amblyopia. I think it is pretty remote, but still I would not
> want to see children receive one eye control and one eye drug.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: I have never seen a myopic child get amblyopic from the
> myopia, that is, if their eyes are perfectly aligned, of course. You
> do see in older individuals who have high degree of myopia something
> which appears to be amblyopia to a mild degree, which probably has to
> do with the fineness or coarseness of the retinal mosaic because of
> the stretching of the retina. I don\'t know what myopia has to do with
> amblyopia if the eyes are perfectly aligned because I have never seen
> it.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: I don\'t really believe there is too much of a risk
> here so I don\'t think this is something we should worry about. But I
> do agree with Dr. West that doing treatment in one eye and not the
> other is probably not the way to go for a number of reasons that I
> won\'t go into.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I don\'t have anything more to add.
>
> DR. GATES: Dr. Feman?
>
> DR. FEMAN: I agree with my colleagues, but let me just add one other
> aspect. This is the reason why I thought we would need to be
> evaluating both eyes in the children whenever they came back for the
> repeat part of the study, rather than just doing one eye evaluation
> because of the fear that there may be something developing that you
> are not picking up.
>
> DR. BULLIMORE: Just to clarify my one eye comment earlier, I wasn\'t
> advocating treating one eye; I was just, from a statistical and
> practical point of view, assessing the outcome in one eye only. I
> apologize for any confusion.
>
> DR FEMAN: I understand, but what I am getting at is that we need to
> assess the outcome in both eye because of the slight risk. Even though
> you are treating both eyes, you are treating a child that potentially
> has a chance to develop amblyopia. We don\'t know what is happening in
> their home and I think you need to be assessing both eyes every time
> the child comes in.
>
> DR. GATES: Dr. West, do you have a comment?
>
> DR. WEST: I think that Dr. Feman is correct and that it may be easier
> for the parent to get it in the first eye or the second eye. There may
> be more of an effect in one eye due to differences in the way the
> medication is administered.
>
> DR. GATES: Any other comments? I am most comfortable with both eyes
> being treated and followed. I know that amblyopia would be an
> extremely low risk but that is not acceptable to my thinking. Dr.
> Gorman?
>
> DR. GORMAN: Disagreeing with my learned colleagues, I am still
> intrigued by the one eye study in older children once they have become
> at least partially visually mature. With this rate of follow-up that
> we have suggested with six months of refractive exam, I think the
> chance of developing such a difference in refractive error as to
> develop amblyopia would be minimized, and it would be the most rapid
> way of showing a treatment effect because you would see divergence
> between the progression in two eyes with each person acting as their
> own control.
>
> On the issue of examining both eyes, I think that there is an absolute
> need to examine both eyes. If 85 percent of the American population is
> right-handed there is a chance that just that one factor alone will
> influence which eye you are more effective in getting the medicine in.
> If you are preferentially always putting it in one eye prior to the
> other, there is a chance of having a different treatment effect.
>
> DR. MILLER: I have changed my thinking listening to the people here. I
> don\'t think there is really any chance of getting amblyopia on a
> refractive basis because we are excluding anisometropia from the
> beginning. So, they are going to be in the same ball park whatever
> happens with the medicine. But if there is a cycloplegic effect from
> the medicine that is significant, we do know that if we treat kids
> with atropine there is the potential of inducing amblyopia in the
> treated eye. So, we should be following both eye and just making sure
> that the best corrected vision remains good throughout the study,
> mostly because we are treating healthy kids.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Well, strictly answering the question, I don\'t know what
> \"prior\"\--how early that means. But it seems that in general, as the
> others have said, the risk of amblyopia in the parameters that we have
> discussed is very low. So, I don\'t think that it is a big risk and I
> don\'t think it should be limited to older children.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: I will pass.
>
> DR. GATES: Any other comments on question 14? Then we will move on.
> Question 15, given the potential for wide use in a pediatric
> population, what level of adverse events should clinical trials in
> this area be designed to detect, 1 percent, 0.5 percent, 0.1 percent,
> 0.05 percent, 0.01 percent, 0.001 percent, 0.0001 percent? We will
> begin the discussion again with Dr. West.
>
> DR. WEST: What type of adverse event are we discussing? Are we
> discussing burning on installation or are we talking about something
> that is sight- or life-threatening? Are we talking about an SAE or
> not?
>
> DR. CHAMBERS: Just the ability to pick up any adverse event; in fact,
> to study enough patients to even note low frequency adverse events.
>
> DR. BULLIMORE: From the point of view of the agency, could you define
> adverse event and differentiate it from a complication?
>
> DR. CHAMBERS: They are the same as far as the agency is concerned.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I haven\'t done this before, what levels do you usually
> use as your standard in similar trials? Because I think we should be a
> little bit on the strict side because we are doing healthy children.
>
> DR. CHAMBERS: The ICH guidance documents say in general that we should
> be treating, in the overall drug development, at least 1,500 patients
> and should be treating 300-600 patients at least for the initial
> duration, and 100 patients for six months for long-term therapies.
> From an ophthalmology perspective, we generally have had an absolute
> lower limit of 300 patients studied during the duration that you
> expect to go on in order to be able to determine a one percent adverse
> event rate. If you study 300 patients you have a 95 percent chance of
> detecting one event at a one percent rate. So, if you study 300
> patients the odds are you will see at least one patient with an event.
> Whether you will recognize that that was really attributable to the
> drug or not because of one event is questionable but the odds are that
> will come up. If you wanted to look for events that are lower than
> that, you have correspondingly higher numbers of people you need to
> study.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: Just for clarification, if you have a condition that might
> occur, like a retinal detachment, in 1/1,000 or 1/500, how does that
> relate to this? Would that 1/1,000 be 0.1 or is it more complicated
> than that?
>
> DR. CHAMBERS: No, that is correct, 1/1,000 would be 0.1 percent. If
> you wanted to make sure that you were going to at least see one of
> those cases you would need to study 3,000 patients. There is a direct
> relationship between these percentages and the number of patients you
> would need to study in the overall program.
>
> DR. GATES: Dr. West?
>
> DR. WEST: So, then now I can answer? So, I would say that it depends
> upon the event that you are looking for, especially since you are
> treating healthy children. If an adverse event is as meager as burning
> on installation, I would like to know about that, but if this is a
> muscarinic antagonist and if it caused bowel obstruction that was
> severe enough to kill the child, I would want to know at a frequency
> of, you know, 1/10,000 or 1/100,000. I mean, suppose you gave eye
> drops to prevent myopia and you killed kids with bowel obstructions?
>
> DR. CHAMBERS: The difficulty is we won\'t know before the trial
> runs\--
>
> DR. WEST: Right.
>
> DR. CHAMBERS: \--what events we are looking for. I mean, we tell
> people to look for everything but we don\'t know ahead of time what
> events or at what frequency they are likely to occur.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: I think there is another layer of complexity that we
> haven\'t begun to address. If I had to guess, the most common adverse
> event from this agent will be eye burning or eye irritation. It will
> be followed by conjunctivitis, a disease I see in my population every
> day without taking drops. Then there will be some number of corneal
> lacerations from getting the applicator too close to the eye in a
> struggling 6 year old. Then there will be some small but probably real
> global punctures from this particular administration, especially in
> year 6 when I just don\'t want to do this anymore. All those
> things\--because the eyes are so emotionally charged for most parents,
> you know, it is one of those organ systems that is very emotionally
> charged\--are going to get reported with very high frequencies, both
> conjunctivitis and corneal irritations, lid swelling, eye redness so
> that there is going to be a difference between adverse events and
> differences between the rate in the treatment group versus the placebo
> group that is going to make this a lot more difficult. That didn\'t
> answer your question at all, I know.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: One other thing that is important for the committee to
> remember is that while it is very important to understand why adverse
> events might occur and to observe that during the clinical trial,
> after any product is approved there is a safety surveillance. Now, it
> is not as rigorous as what is in the clinical trial but now sponsors
> typically collect all adverse events regardless of how minor. Those
> adverse events are collected, put into a database. Whether or not they
> are related is immaterial. For the first couple of years anyway those
> adverse events are reported on a quarterly basis or very frequent
> basis and then they are reported annually for the duration of the life
> of that product. So, it is not as though when we stop clinical trials
> we stop learning. There is also an ongoing learning process that does
> have an impact in labeling as appropriate. But it is important also to
> realize that that is not done with the same kind of rigor that is done
> in a clinical study.
>
> DR. GATES: Dr. Chambers, if we were looking at an antibiotic in this
> patient population what would be a typical target number?
>
> DR. CHAMBERS: As most things in life, it depends. In the case of
> anti-infectives or antibiotics, it depends on how much we know about
> the compound ahead of time. If it is a product that has already been
> systemically administered at concentrations that are much higher than
> what is going to be given topically, we have not looked for as many
> patients to be treated. That is where we get the more typical 300-500
> number of patients because we have systemic information at a much
> higher concentration. The same is true of some of our beta blockers.
> We have a number of medications that have been studied systemically
> before they ever come to the eye.
>
> For things that are new to the eye, we tend to raise those numbers and
> it depends on what we think the overall potential pharmacological
> activities are and what the population is. Yes, there is a tendency to
> study more patients as we go down in age because we are more risk
> averse.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: In the studies that were done overseas was there any
> preliminary information that would be helpful to us? I haven\'t heard
> anything about that.
>
> DR. CHAMBERS: Except that we are looking for guidance for all
> products, not necessarily this product.
>
> DR. MILLER: Right. So, the answer is there is a range of answers
> depending on how much we know. We don\'t know anything now so we have
> to pick one percent.
>
> DR. GATES: But I still think, even though we are not doing this in
> terms of this one pharmacological agent that has been evaluated
> overseas, that could give us some guidance as to drugs of this variety
> that are being used for this purpose. Do we have any data regarding
> anything like that?
>
> DR. CHAMBERS: Well, any of the compounds we have very rarely start
> just at a Phase III trial. We have some initial information from
> earlier trials but they also tend to be in smaller numbers of
> patients. The issue with rare adverse events is if you don\'t study
> enough people you don\'t really have a chance of seeing them. So, you
> don\'t know what it is you are missing.
>
> DR. BULLIMORE: Basically, study enough patients till you see
> something. I am being facetious, I apologize. If I give you a number
> can I go home? I mean, I think one percent seems reasonable but we are
> being asked to give a number. We have in our mind the protocol given
> by Novartis this morning. I mean, clearly, if this company or another
> company were to come along with something with perhaps a higher risk
> profile than a selective anti-muscarinic, then we might be a little
> bit more concerned. But for the kind of things that are being talked
> about in the context of the data presented today, then one percent
> seems reasonable. If it is stuff with growth factors in there, then
> maybe higher. I don\'t know. Am I going in the right direction, Dr.
> Gorman?
>
> DR. GORMAN: I like the one percent number for a lot of reasons, but
> also realize that for a product that we may be talking about today in
> the sense that it is a \"maybe\" product, you are talking about one
> percent over ten years, which is a really high burden to bear because
> if the product is going to be used for the ten years of developing
> myopia that is going to be a long burden. But I still like that
> number.
>
> I like that number for eye toxicities. I don\'t like that number for
> systemic toxicities. So, the bowel obstructions that were talked
> about, or growth interruption, or intellectual functional loss, or
> school failure, or increased juvenile delinquency, hair loss\--
>
> \[Laughter\]
>
> \--if there are those, I think those numbers have to be less common.
> The benefit is in the eye so I will accept a little more risk in the
> eye but I will not accept as much risk to the rest of the body.
>
> DR. GATES: Yes, Dr. Bull
>
> DR. BULL: I just wanted to revisit a point that Wiley had made
> earlier, and also just to make the distinction between the kinds of
> numbers you would look at if, say, there was a large treatment effect
> you won\'t need a lot of numbers, potentially not need a lot of
> numbers in the studies. There is still a number that you need of
> exposure. I have certainly had applications that have been in for
> review by our divisions that have raised issues just because there
> were not enough people exposed to the product. Even though the study
> design was able to evidence an effect, there was still an issue of
> numerically having enough patients exposed to the product.
>
> You know, just to revisit, we also operate on what are called the ICH,
> International Conference on Harmonization, guidelines which, for
> chronic therapy, advise to have in the ball park for safety purposes
> between 300-600 at six months and a minimum of 100 at 12 months. That
> would be a bit different given that, you know, we are probably looking
> at several years of the trial being under way for these products. So,
> in terms of how long you would need and how many patients you would
> anticipate you would need to enroll because you are probably going to
> have a significant number of dropouts in these kinds of studies as
> well.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: The search for rare events is one of those \"Holy
> Grails.\" Having been involved in the rotovirus study as an
> investigator, there were 5,000 people in the study and we still missed
> the rare events. We were talking about he signal to noise before. The
> signal was there in the clinical data when we went back and looked at
> it the second time with the irritability after the dosing of the
> rotovirus vaccine but we missed it until over a million doses were
> given.
>
> So, I appreciate the agency\'s quest for safety data, but has there
> ever been a study powered, looking at safety of rare events, and the
> answer is no. The International Conference for Harmonization gives you
> guidelines for numbers to look for to make you feel better.
>
> DR. BULL: I would cite as an example that we have had some large
> outcome studies that have been done that have enrolled in excess of
> 10,000. There is one ongoing that has enrolled about 18,000. There are
> studies that are designed to look for rare events.
>
> DR. GORMAN: It is a \"Holy Grail\" that you are not going to reach
> because, no matter how large the study is, when it goes out to a
> million people the next level of rare events is going to rear its ugly
> head. So, I am not sure how rare you want to get. I think a one
> percent number is reasonable to look for in a clinical trial, knowing
> that there is surveillance, both active and passive, after a new drug
> comes out. Your own numbers through the reporting system indicate that
> when a new drug gets released the number of reports of adverse events
> is pretty high. Then, as the drug goes out into use for many years,
> those numbers drop off. People are looking for adverse events\--I am
> not going to say they look for them but they are more aware of adverse
> events when they start using a new drug.
>
> DR. GATES: Dr. West?
>
> DR. WEST: As a parent and a physician, I would be unwilling to accept
> adverse events for a disease that does not kill or maim you. Whereas I
> would be willing to accept serious adverse events for something that
> might save my child\'s life, like a treatment for cancer, if we are
> talking about not needing glasses as much it had better be really
> safe. So, I wouldn\'t necessarily be comfortable with a one percent
> detection. I mean, with the potential widespread use of this, even if
> you didn\'t detect it in your clinical trials, when it was released
> there would be such a large number of doses of this taken that you
> might find some very serious adverse events. So, I think for something
> that is such a benign condition as myopia, our tolerance should be
> less.
>
> DR. GATES: Dr. Gordonson?
>
> DR. GORDONSON: I think one percent is right, as others have said.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: One percent.
>
> DR. GATES: Dr. Chew?
>
> DR. CHEW: I think one percent is reasonable but I think it would be
> good if we had other data in other drugs that give you any sort of
> inkling before you prejudge one percent as being the only one\--if
> there is some inkling of anything that may be possible, then I think
> you have to go to a larger sample size to make sure you are not
> missing that rare event.
>
> DR. GATES: Dr. Feman?
>
> DR. FEMAN: I think one percent is reasonable. We are talking about a
> drug that is going to be applied twice a day to however many hundreds
> of children for a three-year interval approximately and I think one
> percent is going to pick up certainly what we are looking for.
>
> DR. GATES: One percent. Dr. Gorman?
>
> DR. GORMAN: One percent, again realizing it is one percent over ten
> years of therapy. So, over a three-year trial maybe it is a third of a
> percent.
>
> DR. GATES: Dr. Miller?
>
> DR. MILLER: I agree with the one percent. I would love to take under
> advisement any information from overseas trials for whatever drug was
> brought to be investigated, but one percent is what I go with now.
>
> DR. GATES: Dr. Steidl?
>
> DR. STEIDL: I am very concerned about what Dr. West brought up because
> we are basically taking, from my point of view, a relatively healthy
> eye and we are doing something to it in a chronic method. I think we
> really have to be very cautious to be convinced that this is a safe
> product.
>
> Just for a point of clarification, when you say 300, are you talking
> about a total of 600, 300 in each arm, or 3,000 would be a total of
> 6,000? How does that work?
>
> DR. CHAMBERS: We are talking about 300 on drug.
>
> DR. STEIDL: Okay, so it is really double that for the trial.
>
> DR. CHAMBERS: Assuming you have a 1:1 randomization, yes.
>
> DR. STEIDL: I would be tempted to possibly go to 0.5.
>
> DR. GATES: Dr. Plott?
>
> DR. PLOTT: I don\'t have anything else to add.
>
> DR. GATES: Any more discussion on question 15A? We will go on to
> question 15B in the same order. Would this answer change for a product
> which demonstrated a reduction in the frequency of retinal
> detachments? Dr. West?
>
> DR. CHAMBERS: I will just remind you, you threw out those endpoints as
> a potential endpoint. You can continue to answer the question if you
> want, but since you said there wasn\'t an acceptable use of those as
> an endpoint I am not sure that that question has relevance anymore.
>
> DR. WEST: Because that is not our endpoint.
>
> DR. GATES: That is fine. Are there any more comments from the FDA, any
> more questions that we could help with?
>
> DR. CHAMBERS: I just want to make sure there is the opportunity for
> people\--I mean, these are the questions that we came up with prior to
> starting this. If there are comments or if there are other questions
> or other things that you believe we should have talked about or asked,
> we would like to hear that before you leave.
>
> DR. GATES: Dr. Bullimore?
>
> DR. BULLIMORE: We have talked about safety issues without really
> saying what we might do to ensure safety. I threw some things out
> earlier like measuring accommodative function, some tests of near
> vision, monitoring things like school achievement. I mean, if we are
> trying to retard the growth of the eye, is it unreasonable to measure
> the height and weight of the child? I don\'t know. I leave that to the
> pediatricians.
>
> I think measuring visual acuity is important, using an age appropriate
> test; probably measuring uncorrected acuity at least potentially as a
> surrogate measure. We were talking about refractive error and we have
> seen some data on how closely that is related to uncorrected visual
> acuity, but I guess the sponsor should have the option of collecting
> some data to make that point more compelling.
>
> Other things, I mean, I am not suggesting retinal photographs but
> tests of retinal function other than visual acuity that we should be
> doing. Should we be doing tests every year on these kids to make sure
> there are no early retinal changes? I am just thinking aloud, which is
> probably a mistake.
>
> DR. GATES: Dr. Gorman?
>
> DR. GORMAN: With this new class of agents in what is described as a
> healthy population, other than their one disease, I think that the
> performance of this trial without a truly independent data safety
> management committee would be a mistake.
>
> I have talked before about front-loading the safety collection data at
> once a month, and I think that would put to rest a fair number of my
> anxieties about embarking on this new era. I do think myopia is a
> condition that parents will choose to treat, and I do think that there
> is a place for this drug assuming it is effective and has few side
> effects. But until I get to that place I would like to make sure that
> the data for the safety is collected early and often and independently
> reviewed.
>
> DR. GATES: Any other comments? Well, I want to thank you, all, for
> attending today, and I want to thank Novartis for their presentation.
> I want to thank the FDA for their guidance with the questions, and we
> hope that our time was helpful to you, all.
>
> DR. CHAMBERS: Again, I just want to thank everybody for taking the
> time to come and give us your comments, and for all the thought you
> have given before coming, and wish everybody safe travel home. Thank
> you.
>
> DR. GATES: Now we will adjourn.
>
> \[Whereupon, at 4:00 p.m., the proceedings were adjourned.\]
>
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