Download Clinical Endpoints for Retinal disorders

business of retina clinical trials for the retina specialist
Section Editor: Aron Shapiro
Clinical Endpoints for
Retinal Disorders
By Aron Shapiro and Ashley Lafond
B
efore any drug can be approved, marketed, and sold
in the United States, it must undergo extensive testing in large, multicenter clinical trials to demonstrate
efficacy and safety. Approval is predicated on the
successful achievement of endpoints in clinical trials, so the
selection of appropriate endpoints is critical to the development of new therapeutic agents. For any clinical trial, the
efficacy endpoint chosen must be clinically meaningful or
relevant in order to be deemed acceptable by a regulatory
agency. With respect to ophthalmic clinical trials, this may
be a cure or improvement of a disease as defined by resolution or improvement of a patient’s signs and symptoms,
visual function, or a change in an anatomic structure that
has been correlated with visual function.
Although developing standards for clinical trials in ophthalmology sets a basis for meeting adequate safety and
efficacy outcomes, the evolution of medicine requires that
these standards be continually reviewed and potentially
updated. In addition to providing clinical information to
physicians, sophisticated new technologies have the potential to identify onset or progression of retinal diseases by
providing new information on structural changes, which
may lead to better visual outcomes for patients. Although
these technologies may not yet be validated as being correlated with visual function, they provide detailed structural
information and are useful in detecting improvements in
early drug studies. In this column, we review what it means
to choose efficacy endpoints for diseases of the posterior
segment and highlight the importance of choosing endpoints that can appropriately assess the safety and efficacy
of a new drug.
Developing Endpoints
Efficacy endpoints are the crux of any clinical trial, as
they assess the effectiveness of the study intervention. For
the study result to “be acceptable to the medical community, the endpoint needs also to be meaningful—of either
demonstrated or accepted relevance for the population
and interventions of the trial.”1 Other characteristics to
consider include the feasibility of measuring the endpoint,
the reliability of the endpoint measurement, and whether
the endpoint is sensitive to treatment differences and
resistant to bias of both the study subject and the study
24 RETINA Today APRIL 2012
personnel assessing the endpoint.2 The US Food and Drug
Administration (FDA) recommends multiple measures of
visual function as adequate primary endpoints when evaluating the safety and efficacy of new ophthalmic drugs. Some
of these primary endpoints include visual acuity (ability to
resolve high contrast visual angles), visual fields (threshold
detection of a light source emanating from different locations), color vision (ability to distinguish among different
wavelengths of light), and contrast sensitivity (ability to
distinguish among different amplitudes of the same wavelength of light).2,3 The FDA acknowledges that degradation
of these parameters forecasts worsening of functional vision
that will in turn affect the patient’s quality of life.4 Although
trial sponsors always have the option of pursuing different
endpoints, it is the responsibility of the sponsor to then justify the clinical relevance of the new endpoint.3 Effectiveness
of a treatment is demonstrated when there is a sufficient
change in an endpoint that has been determined to be clinically meaningful. Treatments can also be considered effective if the endpoints remain stable, indicating protection
from a clinically relevant decline in vision that is expected
to occur over the observational period of a trial. At the end
of the day, approval will ultimately be based on the risk/
benefit ratio of the intervention and a combination of its
efficacy and safety.
Anatomic Measures
Of particular interest for retinal disorders are measures
that document improvements in a patient’s daily living and
quality of life. Although the FDA currently recommends
that study sponsors use change in visual function as a primary endpoint in measuring the effect of a new treatment
for the eye, anatomic measures such as retinal detachment,
the extent of spread of cytomegalovirus (CMV) retinitis,
the extent of spread of geographic atrophy (GA) expansion,
or the presence of vitreomacular adhesion (VMA) can also
indicate the progression of a disease.
Anatomic endpoints allow for a measure of biologic
activity that visual function assessments may not necessarily pick up, and they can be used as surrogate outcomes
provided that the validated surrogate implies a result on the
true endpoint of interest.1 The key word here is validated:
for the FDA, this means that a structural endpoint shows a
business of retina clinical trials for the retina specialist
strong correlation to current vision or future vision (gain or
loss).4 For example, many clinical studies are now looking at
endpoints for GA that represent clinically significant study
outcomes. GA, the advanced atrophic form of age-related
macular degeneration (AMD), is a significant cause of both
moderate and severe central visual loss. In GA, visual acuity change is often an underestimate of disease progression
because, in early GA, the fovea may be spared while scotomas surrounding the fovea enlarge and interfere with reading and other tasks.5-9 Further, it has been demonstrated
that for eyes with GA and visual acuity between 20/80 and
20/200, the reading rate is inversely correlated with the size
of the GA.10 Patients have further reductions in reading
rate as the GA area enlarges. Inherently, the area of atrophy
measured by fundus photography is a useful endpoint for
clinical trials because an intervention that would slow or
halt the progression of GA would have a positive impact on
daily living activities. This is of utmost importance because,
if GA continues to progress, it will eventually reach the
fovea, leading to almost certain vision loss.
Trials for other retinal diseases, such as vitreomacular
adhesion (VMA), are also utilizing anatomic measures
as clinically relevant endpoints. Occurring as a result of
pathologic posterior vitreous detachment, VMA can lead
to the development of traction-related complications
such as macular holes, AMD, retinal vein occlusions, and
diabetic macular edema. In recent VMA clinical trials, primary endpoints have included the release of vitreomacular
traction, resolution of VMA, and changes in central macular thickness as measured by optical coherence tomography
(OCT).11-14
Anatomic measures, such as structural endpoints, are
useful because they provide an objective measurement that
can be assessed in the clinic by a number of noninvasive
imaging modalities that have been developed specifically
for diseases of the eye. Determining the clinical relevance of
anatomic endpoints is especially important when testing
new therapies for slowly progressing diseases, in which tissue
damage can precede vision loss by several years. And yet,
the validation of anatomic measures for slowly progressing
diseases is inherently a slow process, requiring rigorous and
reproducible research over the course of many years.
New diagnostic technologies such as spectral-domain
OCT and fundus autofluorescence provide ophthalmologists with an enhanced view of the eye and are gaining
attention worldwide. Some new devices are capable of
producing 3-D reconstructions, topographic analyses, and
macular thickness measurements to reveal retinal disease.3
Another addition to the technology realm is the advent
of ultrawide-angle fluorescein angiography. The ability to
image the peripheral retina provides a more comprehensive assessment of the extent of a retinal disease process.
A more complete picture of retinal health may also detect
abnormalities that alter a treatment plan based initially
on a clinical examination and traditional angiography.15
The use of adaptive optics scanning laser ophthalmoscopy
(AO-SLO) has also improved imaging in the retina frontier
as it images the retina in real time. This technology utilizes
adaptive optics to remove optical aberrations from images
obtained from SLO of the retina.16 Reducing aberrations
allows the numerical aperture to be maximized, increasing
light collection and improving both lateral and axial resolution.16 Furthermore, AO-SLO provides high resolution for
clear visualization of individual photoreceptor cells. There
is no doubt that these newer technologies are providing
unprecedented information to clinicians, and, although they
are not yet able to provide approvable endpoints, they offer
more precise information on structural changes for proofof-concept endpoints in early clinical studies.
Conclusion
Choosing the proper efficacy endpoints plays a key
role in the overall design of a clinical trial and the future
of the investigational treatment. Although a vision endpoint is the most important determiner of the efficacy of
a drug, novel endpoints may be necessary in the design
of ongoing and future clinical trials assessing treatments
for retinal diseases. n
Aron Shapiro is Vice President of Retina at
Ora, Inc., in Andover, MA.
Ashley Lafond is a medical writer at Ora, Inc.
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NJ: John Wiley & Sons Inc.; 2007.
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for Retinal Disorders. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycommittee/ucm259087.pdf.
Accessed April 9, 2012.
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Symposium. Invest Ophthalmol Vis Sci. 2008;49(2):479-489.
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Ophthalmology.1989;96(10):1541-1551.
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9. Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related
geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104(10):1677-1691.
10. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central
scotomas from advanced atrophic age-related macular degeneration and Stargardt disease. Ophthalmology.1996;103(9):1458-1466.
11. Intravitreal ranibizumab in exudative age-related macular degeneration with posterior vitreomacular adhesion.
Available at: http://clinicaltrials.gov/ct2/show/NCT00996684. Accessed April 9, 2012.
12. Study of intravitreal microplasmin in relieving vitreo-macular adhesion in neovascular age-related macular
degeneration (AMD). Available at: http://clinicaltrials.gov/ct2/show/NCT00996684. Accessed April 9, 2012.
13. Ocriplasmin for treatment for symptomatic vitreomacular adhesion including macular hole (OASIS). Available
at: http://clinicaltrials.gov/ct2/show/NCT01429441. Accessed April 9, 2012.
14. Trial of microplasmin intravitreal injection for non-surgical treatment of focal vitreomacular adhesion. The MIVITRUST (TG-MV-007) Trial. Available at: http://clinicaltrials.gov/ct2/show/NCT00798317. Accessed April 9, 2012.
15. Kaines A, Oliver S, Reddy S, Schwartz SD. Ultrawide angle angiography for the detection and management of
diabetic retinopathy. Int Ophthalmol Clin. 2009;49(2):53-59.
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ophthalmoscopy. Opt Express. 2002;10(9):405-412.
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