Food and Drug
Administration Public Health
Service DEPARTMENT OF
HEALTH & HUMAN SERVICES
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
This package
includes
1.
The Agency’s briefing summary of clinical information, and
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
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
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
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 ³ 5 and £ 7 diopters?
f) Refractive error of >7
and < 12 diopters?
g) Refractive error of ³12 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?