Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5915_Библиотеки_им_академика_М_И_Перельмана
.pdf
483
19 Regulatory Considerations in Product Development for Back of the Eye
https://t.me/med1917
should not be used during pregnancy unless the potential benefit justifies the potential
risk to the fetus.
The BLA application for LUCENTIS™ contained clinical data from seven trials
that investigated the pharmacokinetics and pharmacodynamics of ranibizumab in
humans at doses ranging from 0.05 to 2 mg. All clinical trials were conducted using a
bolus Intravitreal injection of the drug product in patients with neovascular ARMD.
The primary endpoint was proportion of subjects losing < 15 letters of visual acuity and
the secondary endpoints were the proportion of subjects gaining ³ 15 letters of visual
acuity at 12 months, the mean change from baseline over time in visual acuity score,
and the proportion of subjects with a Snellen equivalent visual acuity of 20/200 or
worse. Clinically meaningful and statistically significant benefits were seen in the primary endpoint at both 0.3
and 0.5 mg doses administered intravitreal over 12 months.
Both doses were equally effective and showed a substantial benefit compared to control
with the 0.5 mg dose providing a slightly better outcome in the proportion of subject
gaining ³ 15 letters and the mean change in visual acuity score from baseline at 12
months. The ocular safety profile was favorable and key serious ocular adverse events
appeared to be related largely to conjunctival anesthetic and intravitreal injection procedures. Following the BLA application, LUCENTIS™ was approved in June 2006.
19.7 Summary
To date, regulatory guidance specifically geared towards the development of posterior segment therapies has not been issued. However, a good understanding of the
standard drug product approval process, the various regulatory guidelines, and specific ocular nonclinical and clinical programs provides a blueprint for success.
Furthermore, a review of the summary basis of approvals (SBAs) for products that
have been evaluated and approved by the FDA and/or other health agencies around
the world is also helpful in comprehending the nature of these drug development
programs. In addition, it is crucial that the sponsor interacts with the health authorities throughout the course of the drug development program to ensure that the program is on the right track for success. As we develop new and improved drug
candidates for the treatment of various posterior ocular segment diseases with the
help of cutting edge science, it is of utmost importance that we do so within the
confines of each country’s ethics and regulation, and with the ultimate goal of
improving patient health and quality of life, in sight.
References
Clark AF, Yorio T (2003) Ophthalmic drug discovery. Nat Rev Drug Discov 2(6):448–459
Draft FDA Guidance for Industry: Adaptive design clinical trials for drugs and biologics. Feb 2010
(http://www.fda.gov/downloads/Drugs/guidancecomplianceregulatoryinformation/guidances/
ucm201790.pdf)
484 A.A. Kulkarni
https://t.me/med1917
Draft FDA Guidance for Industry: Applications covered by Section
505(b)(2). Oct 1999 (http://
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm079345.pdf)
Drug Approval Package: LUCENTIS™ (Ranibizumab) Injection. Approval Date – 06/30/2006
Drug Approval Package: OZURDEX™ (Dexamethasone Intravitreal Implant). Approval Date
– 06/17/2009
Drugs @ FDA available on the FDA Website at
http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/index.cfm
Edelman JL, Lutz D, Castro MR (2005) Corticosteroids inhibit VEGF-induced vascular leakage in
a rabbit model of blood-retinal and blood-aqueous barrier breakdown. Exp Eye Res
80(2):249–258
FDA Guidance for Industry, Content and Format of Investigational New Drug Applications (INDs)
for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnologyderived Products, November 1995 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071597.pdf)
FDA Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products.
Feb 2000 (http://www.fda.gov/cder/guidance/index.htm).
Ghodes DM, Balamurugan A, Larsen BA, Maylahn C (2005) Age-related eye diseases: an emerging
challenge for public health professionals. Prev Chronic Dis 2(3):A17
Gordon DM (1959a) Dexamethasone in ophthalmology. Am J Ophthalmol 48:656–660
Gordon DM (1959b) Dexamethasone in ophthalmic disorders. Ann N Y Acad Sci 82:1008–1011
Gryziewicz JL, Whitcup SM (2006) Regulatory issues in drug delivery to the eye. In: Intraocular
drug delivery, 1st edn
Gryziewicz L (2005) Regulatory aspects of drug approval for macular degeneration. Adv Drug
Deliv Rev 57(14):2092–2098
Lee SS, Robinson MR (2009) Novel drug delivery systems for retinal diseases: a review. Opthalmic
Res 41(3):124–135
Marra M, Gukasyan HJ, Raghava S, Kompella UB (2007) 2
nd
Ophthalmic drug development and
delivery summit. Expert Opin Drug Deliv 4(1):77–85
Chapter 20
https://t.me/med1917
Clinical Endpoints for Back of the Eye Diseases
Karl G. Csaky
Abstract The development of new drugs and drug delivery devices for the treatment
of posterior eye diseases is critically dependent on the potential for that drug to be
approved by the United States Food and Drug Administration (FDA). This approval
process is predicated on the successful achievement of endpoints in large multicenter clinical trials. This chapter will discuss the history and evolving nature of
endpoints for these clinical trials. Updates on recent novel endpoints will be
discussed as well as the potential for the use of readouts from various imaging tools
of the retina as FDA acceptable endpoints for clinical trials.
20.1 Background
For any new drug to marketed and sold in the United States, it must undergo extensive testing in clinical trials and ultimately be approved by the FDA. The FDA
approves drugs based on adequate information that demonstrates both the drug’s
efficacy and safety. While this authority derives from the Federal Food Drug and
Cosmetic Act this law allows a large amount of discretionary power to the FDA to
determine what standards a drug needs to meet for adequate safety and efficacy.
While the FDA has established many standards for both these outcomes, the evolution of medicine requires that many of these standards be continually reviewed and
potentially updated. As will be noted below as new drugs for the treatment of retinal
diseases are evaluated, approved and brought into clinical practice newer guidelines
for approvability of a novel therapeutic evolve as well. This point as it pertains to
therapeutics for retinal diseases will be discussed in this chapter.
K.G. Csaky (*)
Sybil Harrington Molecular Laboratory, Retina Foundation of the Southwest,
9900 N. Central Expressway, Suite 400, Dallas, TX 75231, USA
e-mail: kcsaky@retinafoundation.org
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_20,
© American Association of Pharmaceutical Scientists, 2011
485
486
K.G. Csaky
https://t.me/med1917
The rate of development over the last 10 years of multiple therapies for retinal
diseases has been enormous. In contrast until the year 2000 therapies for the vast
majority of retinal diseases were limited to either retinal or cryo-destructive
procedures. While the approach using two modalities of treatment appeared restrictive, the treatments were also recommended for use based on sound clinical trial
data. For example, laser therapy had been demonstrated in elegant multicenter
randomized clinical trials to be beneficial for diabetic proliferative retinopathy
(1979), diabetic macular edema (1985), retinal neovascularization and macular
edema associated with branch retinal vein occlusion (Finkelstein 1986) and choroidal
neovascularization occurring in the setting of age-related macular degeneration
(1991). In addition, cryotherapy had been demonstrated to prevent long-term vision
loss in premature infants developing retinopathy of prematurity (1990). Interestingly,
all of the above clinical trials were supported by the National Institutes of Health
and utilized an approved medical device, laser photocoagulation, or cryotherapy.
As such, additional FDA approval was not required to allow laser or cryo-therapy
to be used in the above diseases.
20.2 FDA Endpoints
This background is important to understand the role that the FDA played in the
development of therapies for retinal diseases. The concept of FDA approval was not
part of the retinal lexicon until the advent of photodynamic therapy. However the
numerous clinical trials that were undertaken prior to 2000 did set the stage for the
requirements that were subsequently embraced by the FDA for drug approval for
the treatment of retinal diseases. For example, the use of the binary outcome of the
percentage of patients with a worsening of 15 or more letters was used as an endpoint for the approval of verteporfin for neovascular age-related macular degeneration (1999) primarily based on the fact that 15 letters represents a doubling of the
visual angle using ETDRS visual acuity testing. The ETDRS chart consisted of fiveletter lines that have a geometric progression from line to line with every third line
representing a doubling of the size of the letters. The ETDRS chart was developed
for the Early Treatment and Diabetic Retinopathy study (Beck et al. 2007).
20.3 Endpoints for Neovascular Age-Related
Macular Degeneration (Table 20.1)
The clinical trial for evaluation of the efficacy of verteporfin in neovascular AMD
completed in 2000 was termed the TAP trial (Treatment of Age-Related Macular
Degeneration with Verteporfin Therapy) and demonstrated that 61% of verteporfintreated eyes compared to 46% of placebo-treated eyes had lost fewer than 15 letters
487
20 Clinical Endpoints for Back of the Eye Diseases
https://t.me/med1917
Table 20.1 Endpoints for approved agents for neovascular age-related macular degeneration
Drug Primary endpoint Secondary endpoints Anatomic endpoints
Verteporfin 15 or more letter
loss rate
Pegaptinib 15 or more letter
loss rate
Ranibizumab 15 or more letter
loss rate
15 or more letter
gain rate
15 or more letter
gain rate
15 or more letter
gain rate; mean
vision change
Growth of choroidal
neovascularization
Growth of choroidal
neovascularization
Size of choroidal
neovasularization,
leakage
of visual acuity from baseline (1999). Subsequently, in 2004, the VISION trial
demonstrated that the anti-VEGF agent pegaptinib reduced the rate of 15 letters of
vision loss from 45% in the control group to 30% in the pegaptinib group (Gragoudas
et al. 2004). And finally, in 2006, approval of ranibizumab was based on two clinical
trials, the ANCHOR trial, for subjects with predominately classic choroidal neovascularization, and the MARINA trial, for subjects with minimally classic choroidal
neovascularization. The FDA-mandated primary outcome was followed with the
ANCHOR trial showing that 95% of ranibizumab-treated subjects compared with
65% of subjects in the verteporfin-treated group lost fewer than 15 letters (Brown
et al. 2006). In the MARINA trial, 95% of ranibizumab-treated subjects compared
with 62% of subjects in the sham-injected group lost fewer than 15 letters (Rosenfeld
et al. 2006).
20.4 FDA Guidelines for Other Retinal Diseases
A vision endpoint is the most important determiner of the efficacy of a drug; however, the strict guidelines imposed by the FDA for approvability while practical in
diseases with the potential for rapid loss of vision such as neovascular AMD might
not be easily applicable to other diseases such as retinal vein occlusion or diabetic
retinopathy. Additionally once it was demonstrated that less than 5% of subjects
with neovascular AMD lose 15 or more letters of vision while on ranibizumab, this
endpoint became limiting for future trials in neovascular AMD attempting to
improve on the efficacy of ranibizumab.
Thus in 2007, the National Eye Institute along with the FDA took part in a 2-day
symposium discussing various issues related to clinical trial design and endpoints
for retinal disease (Csaky et al. 2008). When considering the issue of valid endpoints or clinical design issues a few terms require clarification. A biomarker, as
defined by the Biomarkers Definitions Working Group, is “a characteristic that is
objectively measured and evaluated as an indicator of normal biological processes,
pathogenic processes, or pharmacologic responses to a therapeutic intervention.” In
the discussion of valid endpoints, it is safe to say that biomarkers should be able to
predict known endpoints and would then have their greatest value in serving as
surrogate endpoints in clinical trials. A surrogate endpoint, then, is a biomarker that
488
K.G. Csaky
https://t.me/med1917
is “reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or
other evidence to predict clinical benefit.” Therefore, the best surrogate endpoint is
a biomarker that changes along with a clinical endpoint. The classic example of a
valid biomarker that serves as an FDA-approved surrogate endpoint is the CD4 cell
count. This biomarker, the CD4 count, has been demonstrated to change in response
to an efficacious therapy for AIDS and thus serves as a surrogate endpoint.
Additionally, a clinical endpoint, as defined by the Biomarkers Definitions Working
Group is “a characteristic or variable that reflects how a patient feels, functions, or
survives.” While a primary endpoint is defined as the main result that is measured
at the end of a study to see if a given treatment works. The primary endpoint must
always be chosen before a clinical trial begins. And finally, most relevant to clinical
trials of the retina, is the term anatomic endpoint. This term refers to an anatomic
feature that is measured at the end of a study to assess whether a given treatment
works. While an anatomic endpoint might serve as the primary endpoint of a trial in
retinal clinical trials, anatomic endpoints serve primarily to support the results of
the primary visual clinical endpoint.
As mentioned above novel endpoints may be necessary in design of on-going
and future clinical trials studying treatments for retinal diseases. One area that has
received significant attention is the design of clinical trials for diabetic retinopathy.
While newer agents are already in the clinic for neovascular AMD such is not the
case for diabetic retinopathy. One of the issues has been the requirement of the FDA
that all diabetic retinopathy trials be continued for at least 36 months. This requirement is based on the observation in the Diabetic Complications and Treatment Trial
that early results of a treatment for diabetic retinopathy may not predict outcomes at
36 months. Indeed within that DCCT, subjects in the intensive therapy group were
noted to have a worsening of their retinopathy in the first 2 years but then remained
stable while subjects receiving conventional therapy for diabetes worsened at a
steady rate with a crossing of the outcomes from the intensive group at 2 years and
then subsequent worsening at 3 years. However, recognizing that a 36-month clinical
trial may be unduly burdensome to complete, the FDA did offer the possibility that
effectiveness of a drug could be demonstrated in a 24-month trial. In this endpoint
scenario a two-time point comparison with consistent slopes at both time points
would have to be demonstrated. In other words, the two time point comparisons
would have to be numerically noninferior with clinical and statistical superior differences at 24 months when compared with the original baseline (Csaky et
al. 2008).
This approach would have special importance for evaluations of therapies for diabetic
macular edema. Indeed, recently it was announced that two trials evaluating the
ability of an injectable nonerodible polymer containing fluocinolone acetonide
(Iluvein) for diabetic macular edema has demonstrated success in attaining the
endpoint of the percentage of patients with improved visual acuity of 15 or more
letters at month 24 (Alimera Sciences Press Release Dec 23 2009). As required by
the FDA, the study will continue for an additional 12 months beyond the primary
endpoint to assess further measures of both efficacy and safety.
Another point of potential endpoint adjustment by the FDA would be clinical
trials designed to evaluate therapeutic agents for proliferative retinopathy. In the
489
20 Clinical Endpoints for Back of the Eye Diseases
https://t.me/med1917
NEI/FDA symposium the FDA raised the possibility that clinical trials for neovascular
diabetic subjects may be able to utilize an anatomic endpoint, the development of
retinal or disc neovascularization, as a primary endpoint. This anatomic outcome
was determined as a possibility because there exists a plethora of data that has
demonstrated that the onset of retinal neovascularization invariably is associated
with loss of vision. As such, trials utilizing the development of neovascularization
as an endpoint might be acceptable (Csaky et al. 2008). This could well enhance the
ability to bring drug to the markets that target the angiogenic process in diabetic
retinopathy.
20.5 Endpoint for Geographic Atrophy
Another disease for which therapeutic agents are in clinical trials is geographic
atrophy secondary to age-related macular degeneration. This disease represents
another example where the potential for a more attainable endpoint would allow for
the evaluation of novel therapeutics for a disease. As the natural history of geographic atrophy is one of slow deterioration the endpoint most accepted by the FDA,
the percentage of subjects with a 15-letter vision loss, would have required trials
lasting many years. However in consultation with experts, it became clear that loss
of retinal tissue is always considered a bad outcome regardless of the immediate
effect on vision. Therefore, the FDA is now considering the loss of retinal tissue as
a primary endpoint for trials studying geographic atrophy (Csaky et al. 2008).
However, determination of the proper imaging modality to best evaluate the extent
of retinal tissue loss remains elusive with on-going studies determining the reproducibility and reliability of fundus photography, fundus autofluorescence
(Fleckenstein et al. 2010), and spectral domain optical coherence tomography.
20.6 Endpoint for Retinal Vein Occlusion
And finally in the story of evolving endpoints comes to the development of novel
therapeutics for retinal vein occlusion. As no effective treatments for central retinal
vein occlusion existed, including laser, the FDA reviewed trial designs for this
disease and determined that a novel endpoint, time to achieve a 15 letter or improvement in best-corrected visual acuity, could be used. This decision allowed for a
much shorter time frame for these clinical trials to occur. As a result a novel
bioerodible polymer liberating dexamethasone (Ozurdex®) was approved (Haller
et al. 2010). For the evaluation and subsequent approval of ranibizumab for the
treatment of retinal vein occlusion, the FDA allowed for a comparison of mean
change from baseline in best-corrected visual acuity at 6 months. Indeed, in the
ranibizumab trial for branch retinal vein occlusion, 61% of subjects receiving
monthly ranibizumab, compared with 29% in the sham injected arm, gained 15 or
490
K.G. Csaky
https://t.me/med1917
Table 20.2 Endpoints for approved agents for retinal vein occlusion
Disease Trial Primary endpoint
Neovascular AMD ANCHOR, MARINA Rate of 15 or more letter loss rate
Retinal vein occlusion BRAVO, CRUISE Mean change in visual acuity from
baseline to 6 months
Retinal vein occlusion GENEVA Time to 15 or more letter gain
more letters at 6 months (Genentech Press Release June 22 2010). In subjects with
central retinal vein occlusions, 48% of subjects receiving monthly ranibizumab,
compared with 17% in the sham injected arm, gained 15 or more letters at 6 months
(Genentech Press Release June 22 2010) (Table 20.2).
20.7 Future Endpoints
Many new technologies (e.g., spectral domain optical coherence tomography
(SD-OCT), fundus autofluorescence) are allowing retina specialists to image the
retina in ways never before possible. Detailed topographic and anatomical scans can
provide high-resolution images of cross-sections of the retina. In many cases,
accompanying software allows for the generation of 3-D reconstructions, topographic analyses, and more precise macular thickness measurements including
quantitative segmentation of various layers of the retina (Oster et al. 2010). While
providing clinical information to physicians, these instruments also have the potential to provide data that might serve as endpoints in clinical trials (Browning et al.
2009). For example, as described earlier the degree of retinal tissue loss seen in
geographic atrophy is now being considered as a valid endpoint for trials evaluating
therapies for geographic atrophy (Csaky et al. 2008). In the case of geographic atrophy this is critical because the progressive loss of retinal tissue in geographic
atrophy does not always immediately involve the fovea (Sunness et al. 2008) so
there may be no initial direct effect on the visual acuity. However, the FDA appreciates that loss of macular retinal tissue is a bad outcome and therefore this agency
would consider approving agents that slow this tissue loss without requiring that a
direct effect on visual acuity be demonstrated. However, as with all new imaging
technologies, the questions that are raised focus on what the imaging tool is actually
demonstrating. For example, Fig. 20.1 demonstrates a fundus autofluorescence
image of a patient with geographic atrophy. The central dark spot is thought to be
due to loss of autofluorescence from the retinal pigment epithelium (Sunness et al.
2006). However, it has been demonstrated that in some cases of diminished retinal
autofluorescence the retinal pigment epithelium and overlying photoreceptor are
viable and it is simply the loss of autofluorescent pigment with the retinal pigment epithelium that is responsible for the diminished autofluorescent signal
(Brar et al. 2009; Schmitz-Valckenberg et al. 2010). Therefore, it may very well be
that additional confirmatory imaging of the retina by SD-OCT (Fig. 20.2) will be
491
20 Clinical Endpoints for Back of the Eye Diseases
https://t.me/med1917
Fig. 20.1 Fundus autofluorescence of a patient with extensive geographic atrophy demonstrating
a central area of decreased autofluorescence and surrounding normal pigment epithelial
autoflourescence
Fig. 20.2 Spectral domain optical coherence tomography of a subject with geographic atrophy
demonstrating loss of photoreceptors (arrows) and pigment epithelium (asterisk) but maintained
retinal structures in the surrounding areas (arrowheads) (IR inner retina; PR photoreceptors; IS/OS
inner segment/outer segment junction; RPE retinal pigment epithelium; Chor choroid)
required to confirm loss of retinal tissue as demonstrated by standard retinal
autofluorescence.
Another problem with the use of anatomic imaging tools and that changes that
are seen and measured on the above instruments are not always correlated to visual
492
K.G. Csaky
https://t.me/med1917
function. Measures of anatomic changes are already being used to support an
indication of a treatment effect, but data to date suggests a poor correlation with
many aspects of OCT measurements and visual acuity (Fleckenstein et al. 2010).
Therefore, it is not clear how and when OCT findings will be used as a surrogate
outcome for visual function. But as these new imaging modalities are further tested
alternative anatomic measures, such as integrity of the inner segment/outer segment
junction, may prove to be more precise predictors of visual acuity (Oster et al.
2010). The future of these more rapidly measurable endpoints portends an exciting
future for the development of treatments for retinal diseases.
References
Alimera Sciences Press Release Dec 23 (2009) Alimera Announces Positive Results from the
Two Phase 3 Fame™ Trials of Iluvien
alimerasciences.com/News/2009PressReleases/tabid/106/ItemID/48/Default.aspx
Anon (1979) Four risk factors for severe visual loss in diabetic retinopathy. The third report from
the Diabetic Retinopathy Study. The Diabetic Retinopathy Study Research Group. Arch
Ophthalmol 97:654–655
Anon (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy
Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch
Ophthalmol 103:1796–1806
Anon (1990) Multicenter trial of cryotherapy for retinopathy of prematurity. One-year outcome–
structure and function. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch
Ophthalmol 108:1408–1416
Anon (1991) Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for
evaluation and treatment in the macular photocoagulation study. Macular Photocoagulation
Study Group. Arch Ophthalmol 109:1242–1257
Anon (1999) Photodynamic therapy of subfoveal choroidal neovascularization in age-related mac-
ular degeneration with verteporfin: one-year results of 2 randomized clinical trials–TAP report.
Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study
Group. Arch Ophthalmol 117:1329–1345
Beck RW, Maguire MG, Bressler NM, Glassman AR, Lindblad AS, Ferris FL (2007) Visual acuity
as an outcome measure in clinical trials of retinal diseases. Ophthalmology 114:1804–1809
Brar M, Kozak I, Cheng L, Bartsch DU, Yuson R, Nigam N, Oster SF, Mojana F, Freeman WR
(2009) Correlation between spectral-domain optical coherence tomography and fundus autofluorescence at the margins of geographic atrophy. Am J Ophthalmol 148:439–444
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S (2006)
Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J
Med 355:1432–1444
Browning DJ, Apte RS, Bressler SB, Chalam KV, Danis RP, Davis MD, Kollman C, Qin H, Sadda S,
Scott IU (2009) Association of the extent of diabetic macular edema as assessed by optical
coherence tomography with visual acuity and retinal outcome variables. Retina 29:300–305
Csaky KG, Richman EA, Ferris FL 3rd (2008) Report from the NEI/FDA Ophthalmic Clinical
Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 49:479–489
Finkelstein D (1986) Argon laser photocoagulation for macular edema in branch vein occlusion.
Ophthalmology 93:975–977
Fleckenstein M, Adrion C, Schmitz-Valckenberg S, Gobel AP, Bindewald-Wittich A, Scholl HP,
Mansmann U, Holz FG (2010) Concordance of disease progression in bilateral geographic
atrophy due to AMD. Invest Ophthalmol Vis Sci 51:637–642
®
in Patients with Diabetic Macular Edema. http://www.
Соседние файлы в папке Библиотека им академика М.И. Перельмана