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September 2003

To Advisory Committee Meeting Participants:

This document is the FDA's background package for the Ophthalmic
Sub-Committee Meeting of the Dermatologic and Ophthalmologic Advisory
Committee Meeting to be held on

September 25, 2003, at the Gaithersburg Holiday Inn. The topic for
discussion is the study design of trials in the treatment of myopia.

This package includes

1.  The Agency's briefing summary of clinical information, and

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2.  Draft questions for discussion at the meeting.

Please direct any question concerning the meeting to Kimberly Littleton
Topper, Advisors and Consultants Staff, at (301) 827-6755.

**Ophthalmic Sub-Committee Meeting**

**Dermatologic and Ophthalmologic Advisory Committee**

**September 25, 2003**

The Agency is seeking guidance from the Advisory Committee on the
development of drug therapies to prevent or slow the progression of
myopia.

An available therapy for myopia would carry important public health
implications. The prevalence of myopia in the U.S. has been estimated at
20-50%[^1]. It is not unrealistic to believe that parents will "demand"
myopic prevention treatment for their child if they are under the
impression that their child will benefit. This could result in
unprecedented pediatric exposure to a chronically administered drug in a
population of otherwise healthy children.

Several issues require consideration before a precedent for acceptable
clinical trial criteria is set. Discussion toward developing an
evidence-based approach is sought.

# Natural History of Myopia

The long-term natural history of myopia (infancy through adulthood) has
not been well studied. As a result, investigators have relied upon a
variety of studies, frequently cross sectional, to draw inferences about
the effect of myopia on ocular health. These studies have alternately
suggested and refuted a wide variety of associations between myopia,
various retinal diseases and glaucoma.

Even the generally accepted long-term natural history of *high myopia*
is based only on observed anecdotal associations. Despite this absence
of definitive trials, the ophthalmic community at large has accepted
high myopia as an independent risk factor for a variety of retinal
diseases (e.g., retinal tears, holes, detachments, retinopathy, CNV,
etc.). Here, clinicians have brought to bear supportive evidence by
buttressing anecdotally observed associations with speculations about
the pathophysiologic mechanisms involved (e.g., retinal/choroidal
stretching due to increased axial length). In the end, while
associations might be hypothesis-generating, cause and effect can best
be established by conducting large-scale longitudinal, prospective
studies of adequate duration.

## Factors influencing the development of Myopia

There are long standing debates over genetic factors versus
environmental factors as being the primary cause of myopia. Neither
appears able to explain all aspects of the development of myopia.
Differences in ethnicity[^2] have been noted to affect the frequency of
myopia development in the United States. While it may be important to
understand the cause to help select interventions, the failure to
completely understand the cause is not necessarily a fatal flaw to
studying an intervention.

# Issues in Trial Design

The practical issues inherent to the study of myopia prevention make
clinical trial design and implementation difficult. These issues include
the long time span in which non lens‑related refractive changes are
observed (birth through age 30 years), requisite involvement of
children, potential impact of genetic predisposition, educational level,
light exposure, refractive correction, and behavioral patterns such as
the frequency and duration of close work (reading). The long horizon
from enrollment to clinically relevant events and a relatively low
absolute event rate for anything other than a simple refractive error
adds to the difficulty of designing a practical trial.

Therefore, the selected inclusion/exclusion criteria and the selected
primary endpoint are critical to the proper selection of a study
population with a high likelihood of maximizing clinical events.

# Surrogate Endpoints

Clinical trials designed to study diseases with uncertain natural
histories such as myopia often rely on surrogate markers to measure drug
effect. Since no long‑term studies have been conducted to assess the
natural history of myopia, no surrogate marker has been validated as
predictive of clinically relevant ocular disease. As with any proposed
surrogate measure, a scientifically sound argument must be presented
prior to acceptance by the Agency and should include any relevant
preliminary data that might be supportive. Further, the Agency will
ultimately require validation of any proposed surrogate measure.

# Myopia as an Indication

It is unclear to the Agency at what level mild-to-moderate myopia,
absent ocular pathology, is problematic requiring prevention. With the
ability to accommodate intact, refractive errors ranging from +3 to -0.5
diopters provide generally excellent vision for all activities of daily
living. After the ability to accommodate has been lost, refractive
errors between -1 and -2 diopters still provide generally acceptable
vision for most activities of daily living.

# 

# Measure/Definition of Myopia

It is unclear from existing studies whether the cause of myopia is
relevant to a potential pathology. While there is general consensus
among clinicians that an abnormal increase in axial length will
contribute to retinal pathology, it is not clear whether myopia can
cause retinal pathology in eyes of normal axial length. Until more is
known, it seems important to use validated instruments to measure
refractive error, axial length and corneal curvature.

**Draft Questions being considered:**

1)  What is the minimum rate (amount and time) of refractive change that
    determines whether myopia is classified as:

    a.  "Progressive"?

    b.  "Stable"?

    c.  "Regressing"?

2)  Is there an accepted, evidence-based baseline characterization of
    patients who are at high risk of developing progressive myopia?

3)  Which populations should be studied prior to approving a drug
    treatment for prevention or retarding myopia?

    a.  Ages?

    b.  Education levels?

    c.  Ethic groups?

    d.  Family history of myopia?

    e.  Other defining characteristics?

4)  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?

    a.  Minimum axial length?

    b.  Minimum refractive error?

    c.  Minimum corneal curvature?

    d.  Period of time for changes to be observed?

5)  What is the minimum amount of change that would justify a
    pharmacological intervention to arrest its progression?

    a.  Minimum increase in axial length?

    b.  Minimum rate of change in refractive error?

    c.  Minimum change in corneal curvature?

    d.  Period of time for changes to be observed?

6)  What is the minimum amount of change that would is considered a
    pharmacological success in slowing progression?

    a.  Minimum increase in axial length?

    b.  Minimum rate of change in refractive error?

    c.  Minimum change in corneal curvature?

    d.  Period of time for changes to be observed?

7)  "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?

8)  What is an ideal refractive error (or range of refractive errors)?

9)  How much of a refractive change is considered an important change
    for an individual, who would otherwise have had the following
    refraction.

    a.  Refractive error of 1 diopter or less?

    b.  Refractive error of \> 1 and ≤ 2 diopters?

    c.  Refractive error of \> 2 and ≤ 3 diopters?

    d.  Refractive error of \> 3 and ≤ 5 diopters?

    e.  Refractive error of ≥ 5 and ≤ 7 diopters?

    f.  Refractive error of \>7 and \< 12 diopters?

    g.  Refractive error of ≥12 diopters?

10) Which method (or combination of methods) do you consider the most
    reliable and reproducible for the assessment for measuring myopia in
    children

    a.  Automated refraction?

    b.  Cycloplegic refraction?

    c.  Ultrasound axial length measurement?

    d.  Cycloplegic autorefracted spherical equivalent?

    e.  Other?

11) How frequently should assessments be made?

12) Which are clinically relevant, acceptable endpoints of
    myopia-induced ocular disease?

    a.  Development of a retinal tear?

    b.  Development of a retinal detachment?

    c.  Development of a retinal hole?

    d.  Development of lattice degeneration?

    e.  Development of glaucoma? How would glaucoma be defined?

    f.  Development of retinopathy? How would retinopathy be defined?

    g.  Other?

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:

    a.  Duration of treatment?

    b.  Follow-up after treatment?

14) 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?

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 detected (1%? 0.5%? 0.1%, 0.05%, 0.01%, 0.001%,
    0.0001%)? Would this answer change for a product which demonstrated
    a reduction in the frequency of retinal detachments?

[^1]: Saw SM *et al*. Interventions to Retard Myopia Progression in
    Children. *Ophthalmology* *2002*;109:415-427.

[^2]: Kleinstein RN *et al*. Refractive Error and Ethnicity in Children.
    *Arch Ophthalmol.* *2003*;121:1141-1147.