Hindawi
`Journal of Ophthalmology
`Volume 2021, Article ID 6635467, 8 pages
`https://doi.org/10.1155/2021/6635467
`
`Research Article
`Eyes that Do Not Meet the Eligibility Criteria of Clinical Trials on
`Age-Related Macular Degeneration: Proportion of the Real-World
`Patient Population and Reasons for Exclusion
`
`Jae Hui Kim , Jong Woo Kim, and Chul Gu Kim
`
`Department of Ophthalmology, Kim’s Eye Hospital, Seoul, Republic of Korea
`
`Correspondence should be addressed to Jae Hui Kim; kimoph@gmail.com
`
`Received 16 December 2020; Revised 17 March 2021; Accepted 7 April 2021; Published 17 April 2021
`
`Academic Editor: Carlo Cagini
`
`Copyright © 2021 Jae Hui Kim et al. (is is an open access article distributed under the Creative Commons Attribution License,
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Background. To evaluate the proportion of eyes that do not meet the eligibility criteria of clinical trials on neovascular age-related
`macular degeneration (AMD) and the reasons for exclusion. Methods. (is retrospective, observational study included 512 eyes of
`463 patients diagnosed with treatment-na¨ıve neovascular AMD. (e proportion of eyes that did not meet the eligibility criteria of
`the Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies were
`evaluated. (e two most common reasons for exclusion were also evaluated in each subtype of neovascular AMD (typical
`neovascular AMD, polypoidal choroidal vasculopathy (PCV), and type 3 neovascularization). Results. Among the 512 eyes, 229
`(44.7%) did not meet the eligibility criteria. In all the included eyes, the most common reasons for exclusion were good or poor
`visual acuity (169 eyes, 33.0%), followed by the presence of subretinal hemorrhage (47 eyes, 9.5%). Moreover, good or poor visual
`acuity was the most common reason for exclusion in all three subtypes of neovascular AMD. (e second most common reason
`was a fovea-involving scar or fibrosis in typical neovascular AMD, subretinal hemorrhage in PCV, and other vascular diseases
`affecting the retina in type 3 neovascularization. Conclusions. Among the included cases, 44.7% did not meet the eligibility criteria
`for VIEW study, suggesting that the conclusion derived from clinical trials may not directly reflect the real-world outcomes.
`Additionally, the reasons for ineligibility differed among the different subtypes of neovascular AMD.
`
`1. Introduction
`
`Neovascular AMD is one of the primary causes of severe visual
`impairment
`in developed countries [1]. Previously,
`laser
`photocoagulation or photodynamic therapy was used as its
`mainstay treatment. However, the efficacy of these treatment
`modalities has obvious limitations. In 2006, the FDA approved
`anti-VEGF agent, ranibizumab, was introduced [2, 3], followed
`by aflibercept in 2012 [4]. In addition, the off-label use of
`bevacizumab [5] has been widely adopted. (e introduction of
`these anti-VEGF agents has markedly improved the treatment
`outcomes of neovascular AMD, resulting in a significant de-
`crease in the rate of visual loss and blindness [6]. Currently,
`clinical trials are actively being performed to develop better
`treatment methods for neovascular AMD.
`In general, conducting clinical trials is expensive and
`requires years to complete [7, 8]. (erefore, estimating the
`
`time required to complete the planned patient enrollment is
`essential for establishing an efficient clinical trial plan.
`Clinical trials are usually conducted in a controlled envi-
`ronment and have sophisticated eligibility criteria. (us, all
`patients cannot be enrolled into a trial, and some of them, or
`sometimes the majority of them, are excluded on the basis of
`the eligibility criteria.
`Estimation of the proportion of patients in the study
`population who do not meet the eligibility criteria is im-
`portant for several reasons. First, it may help to identify
`whether the results of the clinical trial can be applied to the
`real-world patients. Secondly, it may also help to predict the
`time required to finish the planned patient enrollment. In
`addition, if a particular set of criteria results in the exclusion
`of a relatively large number of patients, patient enrollment in
`future clinical trials could be accelerated by modifying some
`of these criteria. Furthermore, since the characteristics of
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`Journal of Ophthalmology
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`neovascular AMD differ between Asian and Caucasian
`populations [9, 10], obtaining data on Asian populations
`would be of great value.
`(erefore, the purpose of the present study was to
`evaluate the proportion of eyes that do not meet the eligi-
`bility criteria of clinical trials on neovascular AMD among
`the entire sample of eyes diagnosed with treatment-na¨ıve
`neovascular AMD. (e eligibility criteria of the VEGF Trap-
`Eye: Investigation of Efficacy and Safety in Wet AMD
`(VIEW) studies [4], were used for this investigation.
`
`2. Materials and Methods
`(is retrospective, observational study was performed at a
`single center. (e study was approved by the Institutional
`Review Board of Kim’s Eye Hospital and was conducted in
`accordance with the tenets of the Declaration of Helsinki.
`
`only patients aged≥50 years who received intravitreal anti-
`
`2.1. Patients. (e study included consecutive patients di-
`agnosed with treatment-na¨ıve, active neovascular AMD
`between January 2017 and December 2017. Additionally,
`
`VEGF injection after the diagnosis were included in this
`study.
`
`2.2. Examinations and Image Analysis. Measurement of
`best-corrected visual acuity (BCVA) and a clinical exami-
`nation using 90-diopter lens slit-lamp biomicroscopy were
`performed for all the patients, and intraocular pressure was
`measured using a noncontact tonometer. (e fundus pho-
`tographs were acquired using CX-1™ (Topcon, Tokyo, Ja-
`pan). Optical coherence tomography (OCT) images were
`acquired using Spectralis HRA + OCT® (Heidelberg Engi-
`neering GmbH, Heidelberg, Germany) or RS 3000® (Nidek
`Co. Ltd. Tokyo,
`Japan). Fluorescein angiography and
`indocyanine green angiography (ICGA) images were also
`acquired using Spectralis HRA + OCT® (Heidelberg Engi-
`neering GmbH). (e size of the lesion was measured using
`fundus photographs and fluorescein angiography images.
`(e method of classification of neovascular AMD was
`similar to that used in our previous study [10]. (e diagnosis
`of polypoidal choroidal vasculopathy (PCV) was based on
`the ICGA images [11, 12]. Type 3 neovascularization was
`diagnosed using a previously suggested method [13] and was
`identified on the basis of OCT and angiography results. Eyes
`not showing the characteristic features of PCV or type 3
`neovascularization were classified as having typical neo-
`vascular AMD. Patients with definite chorioretinal anasto-
`mosis were classified as having typical neovascular AMD
`because it was uncertain whether the origin of choroidal
`neovascularization was the retina. If ICGA results were
`unavailable or if accurate classification was not possible, the
`patients were considered as unclassifiable. (e ICGA images
`were analyzed by two independent examiners. In case of
`disagreement, the images were reexamined together and the
`disagreement was resolved by mutual discussion between
`the two examiners. Other images, including that of fluo-
`rescein angiography, OCT, and fundus photography, were
`
`evaluated by a single examiner (J.H.K.). (e BCVAs were
`measured using decimal visual acuity chart and subsequently
`converted to logarithm of minimal angle of resolution
`(logMAR) value for further analysis.
`
`2.3. Criteria Used for Analyses. (e eligibility criteria of the
`VIEW studies [4] were classified into three categories as
`follows.
`
`2.4. Category 1: Criteria that Could Not Be Accurately Assessed
`in the Present Study (Table 1). (e present study was a
`retrospective study based on the review of medical records.
`(us, detailed evaluation of the patients’ systemic or ocular
`conditions that are necessary in clinical trials were not
`routinely performed. (erefore, in case of some eligibility
`criteria, it was not possible to accurately assess whether the
`patients met the criteria or not. For example, most of the
`criteria regarding systemic conditions were included in
`category 1.
`
`2.5. Category 2: Criteria Required for Inclusion in the Present
`Study (Table 2). (ese included criteria that should be met in
`order for patients to be included in the present study, e.g.,
`age and prior treatment criteria.
`
`2.6. Category 3: Criteria Used for Result Analysis in the Present
`Study (Table 3). (ese included criteria that were actually
`used for result analysis in the present study. If an eye did not
`meet all three inclusion criteria, or met at least one exclusion
`criterion, that eye was excluded from the clinical trial.
`
`2.7. Analyses. (e results of the examinations performed at
`diagnosis and the patients’ medical history were carefully
`reviewed to identify the proportion of eyes that met each
`category 3 criterion. In addition, the proportion of eyes that
`met category 3 criteria among the three subtypes of neo-
`vascular AMD was compared. (ereafter, the proportion of
`eyes in the top two criteria met by the largest number of
`patients was compared between the different subtypes.
`Lastly, the top two criteria within each subtype group were
`presented.
`For visual acuity analysis, the values of visual acuities
`indicated by the eligible criteria (Table 3) were converted
`into logMAR values as follows: 20/40 � 0.30 (logMAR) and
`20/320 �1.20 (logMAR). (ereafter, the logMAR values
`were used to assess whether visual acuities of the included
`patients met the eligible criteria.
`
`2.8. Statistics. Statistical analyses were performed using
`SPSS for Windows/Macintosh, Version 12.0 (SPSS Inc.,
`Chicago, IL, USA). (e difference in proportion among the
`groups was analyzed using the chi-square test. P values less
`than 0.05 were considered significant.
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`Table 1: Eligibility criteria of the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD studies that could not be accurately
`assessed in the present study (category 1).
`Criterion
`Inclusion Criteria
`1) Willing, committed, and able to return for ALL clinic visits and complete all study related procedures.
`2) Able to read (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a
`family member) and understand and willing to sign the informed consent form.
`3) Signed informed consent form.
`Exclusion Criteria
`4) Significant media opacities, including cataract, in the study eye that might interfere with visual acuity, assessment of safety, or fundus
`photography.
`5) Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the patient
`beyond what is to be expected from standard procedures of intraocular injection or which otherwise may interfere with the injection
`procedure or with evaluation of efficacy or safety.
`6) History of any vitreous hemorrhage within 4 weeks prior to Visit 1 in the study eye.
`7) Any ocular or periocular infection within the last 2 weeks prior to screening in either eye.
`8) Any history of uveitis in either eye.
`9) Presence or history of scleromalacia in either eye.
`10) Previous therapeutic radiation in the region of the study eye.
`11) History of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable
`suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of
`the study or render the patient at high risk for treatment complications.
`12) Participation as a patient in any clinical study within the 12 weeks prior to day 1.
`13) Any systemic or ocular treatment with an investigational agent in the past 12 weeks prior to day 1.
`14) (e use of long acting steroids, either systemically or intraocularly, in the 6 months prior to day 1.
`15) Any history of allergy to povidone iodine.
`16) Presence of any contraindications indicated in the FDA approved label for ranibizumab (Lucentis®; Genentech Inc., South San
`Francisco, CA).
`17) Females who are pregnant, breastfeeding, or of childbearing potential, unwilling to practice adequate contraception throughout the
`study. Adequate contraceptive measures include oral contraceptives (stable use for 2 or more cycles prior to screening); IUD; Depo-
`Provera® (Pfizer, Inc. New York); Norplant® System (Pfizer, Inc. New York) implants; bilateral tubal ligation; vasectomy; condom or
`diaphragm plus either contraceptive sponge, foam, or jelly.
`VEGF � vascular endothelial growth factor, AMD � age-related macular degeneration.
`
`Table 2: Eligibility criteria of the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD studies required for inclusion in the
`present study (category 2).
`Criterion
`Inclusion Criteria
`
`1) Men and women≥50 years of age.
`
`Exclusion Criteria
`2) Any prior ocular (in the study eye) or systemic treatment or surgery for neovascular AMD except dietary supplements or vitamins.
`3) Any prior or concomitant therapy with another investigational agent to treat neovascular AMD in the study eye, except dietary
`supplements or vitamins.
`4) Prior treatment with anti-VEGF agents.
`5) Known serious allergy to the fluorescein sodium for injection in angiography.
`Abbreviations: VEGF � vascular endothelial growth factor, AMD � age-related macular degeneration.
`
`Table 3: Eligibility criteria of the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD studies used for result analysis (category 3)
`and the number of eyes that did not meet the inclusion criteria or that met the exclusion criteria.
`
`Characteristic
`
`Inclusion Criteria
`1) Active primary subfoveal CNV lesions secondary to AMD, including juxtafoveal lesions that affect the fovea as
`evidenced by FA in the study eye.
`2) CNV must be at least 50% of total lesion size.
`3) ETDRS best-corrected visual acuity of 20/40 to 20/320 (letter score of 73 to 25) in the study eye.
`Exclusion Criteria
`
`4) Total lesion size> 12 disc areas (30.5 mm2), including blood, scars, and neovascularization as assessed by FA in the study
`
`eye.
`
`Total
`(N � 512)
`
`8 (1.6%)∗
`25 (4.9%)∗
`169 (33.0%)∗
`
`13 (2.5%)†
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`Table 3: Continued.
`
`Characteristic
`
`5) Subretinal hemorrhage that is either 50% or more of the total lesion area, or if the blood is under the fovea and is 1 or
`more disc areas in size in the study eye. (If the blood is under the fovea, then the fovea must be surrounded 270° by visible
`CNV.)
`
`6) Scar or fibrosis, making up> 50% of total lesion in the study eye.
`
`Total
`(N � 512)
`
`47 (9.2%)†
`
`9 (1.8%)†
`12 (2.3%)†
`2 (0.4%)†
`15 (2.9%)†
`
`7) Scar, fibrosis, or atrophy involving the center of the fovea in the study eye.
`8) Presence of retinal pigment epithelial tears or rips involving the macula in the study eye.
`9) History or clinical evidence of diabetic retinopathy, diabetic macular edema, or any other vascular disease affecting the
`retina, other than AMD, in either eye.
`10) Any concurrent intraocular condition in the study eye (e.g., cataract) that, in the opinion of the investigator, could
`require either medical or surgical intervention during the 96-week study period.
`11) Prior vitrectomy in the study eye.
`12) Any history of macular hole of stage 2 and above in the study eye.
`13) Any intraocular or periocular surgery within 3 months of day 1 on the study eye, except lid surgery, which may not have
`taken place within 1 month of day 1, as long as it is unlikely to interfere with the injection.
`14) Prior trabeculectomy or another filtration surgery in the study eye.
`
`15) Uncontrolled glaucoma (defined as intraocular pressure≥ 25 mmHg despite treatment with antiglaucoma medication)
`
`4 (0.8%)†
`2 (0.4%)†
`0†
`0†
`0†
`2 (0.4%)†
`in the study eye.
`0†
`16) Active intraocular inflammation in either eye.
`0†
`17) Active ocular or periocular infection in either eye.
`18) Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a result of an yttrium aluminum
`0†
`garnet (YAG) posterior capsulotomy) in the study eye.
`0†
`19) History of corneal transplant or corneal dystrophy in the study eye.
`VEGF � vascular endothelial growth factor, AMD � age-related macular degeneration, CNV � choroidal neovascularization, FA � fluorescein angiography,
`
`ETDRS � Early Treatment Diabetic Retinopathy Study.∗: Number of eyes that did not meet the inclusion criteria. †: Number of eyes that met the exclusion
`70.0± 8.9
`neovascular AMD. (e mean age of the patients was 70.0± 8.9
`
`criteria.
`
`3. Results
`During the study period, 512 eyes of 463 patients (282 men
`and 181 women) were newly diagnosed with treatment-na¨ıve
`
`years. Among the eyes, 208 were classified as having typical
`neovascular AMD, 189 as having PCV, and 69 as having type
`3 neovascularization. In the remaining 46 eyes, the subtype of
`neovascular AMD was unclassifiable. Demographic infor-
`mation of the patients is summarized in Table 4.
`Among the 512 eyes, 229 (44.7%) did not satisfy at least
`one inclusion or exclusion category 3 criterion (Table 3):
`171 eyes (33.4%) did not satisfy one criterion, 39 (7.6%) did
`not satisfy two criteria, and 19 (3.7%) did not satisfy three
`or more criteria. Figure 1 shows representative cases of eyes
`did not satisfy the eligible criteria. Among the category 3
`criteria, the top two criteria not met by the patients were the
`visual acuity criterion (Table 3, #3) and submacular
`hemorrhage criterion (Table 3, #5). One hundred sixty-nine
`eyes (33.0%) did not meet the visual acuity criterion; the
`logMAR BCVA at diagnosis was better than 0.30 (Snellen
`equivalents, 20/40) in 95 eyes and worse than 1.20 (Snellen
`equivalents, 20/320) in 74 eyes. Forty-seven eyes (9.2%) did
`not meet the subretinal hemorrhage criterion.
`A comparison among the subtypes of neovascular AMD
`(N � 466) showed that 102 eyes (49.0%) in the typical neo-
`vascular AMD group, 89 in the PCV group (47.1%), and 23
`(33.3%) in the type 3 neovascularization group did not meet at
`least one category 3 criterion (Table 5). No difference was
`observed in the proportion of eyes among the three subtypes
`(P � 0.070). In the analysis including the top two most
`
`282 (60.9%): 181
`(39.1%)
`101 (21.8%)
`225 (43.9%)
`
`Table 4: Demographic information of 463 patients (512 eyes).
`Characteristics
`Age, years
`Sex, men: women
`Diabetes mellitus
`Hypertension
`Subtype of neovascular AMD
`Typical neovascular AMD
`Polypoidal choroidal vasculopathy
`Type 3 neovascularization
`Unclassifiable
`Baseline best-corrected visual acuity,
`logMAR
`
`0.69± 0.54
`Data are presented as mean± standard deviation or No. (%), when ap-
`
`208 (40.7%)
`189 (36.9%)
`69 (13.5%)
`46 (8.9%)
`
`plicable. Abbreviations: AMD, age-related macular degeneration; logMAR,
`logarithm of minimal angle of resolution.
`
`commonly not met criteria, the visual acuity criterion (cate-
`gory 3 criterion #3) was not satisfied in 80 eyes (38.5%) in the
`typical neovascular AMD group, 60 (31.7%) in the PCV group,
`and 17 (24.6%) in the type 3 neovascularization group. (e
`incidence was not significant among the three subtypes
`(P � 0.083). On more specific analysis, there was a significant
`difference in the number of eyes that showed logMAR BCVA
`better than 0.30 (P � 0.032): 40 eyes (19.2%) in the typical
`neovascular AMD group, 44 eyes (23.3%) in the PCV group,
`and 6 eyes (8.7%) in the type 3 neovascularization group. In
`addition, there was a significant difference in the incidence of
`eyes that showed logMAR BCVA worse than 1.20 (P � 0.009):
`40 eyes (19.2%) in the typical neovascular AMD group, 16 eyes
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`
`(a)
`
`(b)
`
`(c)
`
`Figure 1: Fundus photography and optical coherence tomography findings of eyes which did not satisfy the eligible criteria. (a) Best-
`corrected visual acuity better than 20/40, (b) fovea-involving large subretinal hemorrhage, (c) fovea-involving scar.
`
`Table 5: Comparison of the proportion of eyes that did not meet category 3 criteria among the three subtypes of neovascular age-related
`macular degeneration.
`
`value∗
`<0.001
`Data are presented as number (%).AMD � age-related macular degeneration, PCV � polypoidal choroidal vasculopathy.∗Statistical analysis was performed
`
`Characteristic
`
`Eyes that did not meet at least one category 3
`criterion
`Visual acuity criterion
`Visual acuity better than 20/40
`Visual acuity worse than 20/320
`Submacular hemorrhage criterion
`
`using the chi-square test.
`
`Typical neovascular AMD
`(N � 208)
`
`103 (49.5%)
`80 (38.5%)
`40 (19.2%)
`40 (19.2%)
`9 (4.3%)
`
`PCV
`(N � 189)
`
`89 (47.1%)
`60 (31.7%)
`44 (23.3%)
`16 (8.5%)
`31 (16.4%)
`
`Type 3 neovascularization
`(N � 69)
`
`22 (31.9%)
`17 (24.6%)
`6 (8.7%)
`11 (15.9%)
`2 (2.9%)
`
`P
`
`0.036
`0.083
`0.032
`0.009
`
`(8.5%) in the PCV group, and 11 eyes (15.9%) in the type 3
`neovascularization group. (e submacular hemorrhage cri-
`terion (category 3 criterion #5) was not satisfied in 9 eyes
`(4.3%) in the typical neovascular AMD group, 31 (16.4%) in
`the PCV group, and 2 (2.9%) in the type 3 neovascularization
`group. A significant difference was observed in the proportion
`
`of eyes among the three subtypes (P< 0.001).
`
`In the typical neovascular AMD group, the most com-
`mon unmet criterion was the visual acuity criterion (cri-
`terion #3; 80 eyes, 38.5%), followed by the scar, fibrosis, or
`atrophy involving the center of the fovea criterion (criterion
`#7; 11 eyes, 5.3%). In the PCV group, the most common
`criterion not met was the visual acuity criterion (criterion #3;
`60 eyes, 31.7%), followed by the subretinal hemorrhage
`criterion (criterion #5; 31 eyes, 16.4%). In the type 3 neo-
`vascularization group, the most common criterion not met
`was the visual acuity criterion (criterion #3; 17 eyes, 24.6%),
`followed by the other vascular diseases affecting the retina
`criterion (criterion #9; 3 eyes, 4.3%).
`
`4. Discussion
`Although the VIEW study was performed nearly 10 years ago,
`the VIEW study criteria were used in the present study because
`
`aflibercept is one of the most widely used drugs to treat
`neovascular AMD. In the present study, 44.7% of the patients
`newly diagnosed with treatment-na¨ıve neovascular AMD in
`the real-world setting did not meet the eligibility criteria which
`were similar to that of the VIEW studies. (at is, if a clinical
`trial using these eligibility criteria is performed at our insti-
`tution, 44.7% of patients will not pass the screening. However,
`the remaining 55.3% could be potential candidates for the
`clinical trial.
`More importantly, the efficacy of the drug could not be
`tested in 44.7% of the patients in the clinical trial suggesting
`that the treatment efficacy of the drug is unknown in those
`patients. For this reason, further studies are required to evaluate
`the efficacy of the drug in patients with certain characteristics
`that were excluded from clinical trials. For example, since
`patients with submacular hemorrhages were excluded from the
`VIEW studies [4], further clinical trial was performed to
`evaluate the efficacy of aflibercept in this condition [14]. In fact,
`the treatment outcomes were somewhat different between the
`clinical trials [4] and real-world data [15]. Different patients’
`characteristics between the two different conditions may have
`an influence on this difference.
`(e most common criterion that resulted in the ex-
`clusion of the largest number of eyes was the visual acuity
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`criterion; only eyes with an Early Treatment Diabetic Ret-
`inopathy Study (ETDRS) BCVA of 20/40 to 20/320 (letter
`score of 73 to 25) could be included. A similar visual acuity
`criterion was also used in other key clinical trials on neo-
`vascular AMD [2, 16, 17]. In the present study, 169 eyes did
`not satisfy this criterion, accounting for 33.0% of the entire
`study population and approximately 73.8% of the excluded
`cases. (e second most common criterion was the subretinal
`hemorrhage criterion. If an eye exhibited subretinal hem-
`orrhage that affected either 50% or more of the total lesion
`area, or if blood was observed under the fovea and was 1 or
`more disc areas in size, that eye was excluded from the study.
`In the present study, 47 eyes exhibited submacular hem-
`orrhage that satisfied this criterion. (is accounted for 9.2%
`of the entire study population and approximately 20.5% of
`the excluded cases.
`An interesting finding of the present study was that the
`reasons for exclusion differed according to the subtypes of
`neovascular AMD. In all three subtypes, the largest number
`of eyes was excluded by the visual acuity criterion. (e
`proportion of excluded eyes was relatively higher in the
`typical neovascular AMD group (38.5%) than in the PCV
`group (31.7%) or the type 3 neovascularization group
`(24.6%). In addition, the primary reason for exclusion
`differed among the three groups. Particularly, in the PCV
`group, majority of eyes were excluded because of good visual
`acuity, and only a small proportion of eyes were excluded
`because of poor visual acuity.
`A significant difference was observed in the proportion
`of eyes excluded because of the subretinal hemorrhage
`criterion. (e proportion was markedly higher in the PCV
`group (16.4%) than in the typical neovascular AMD group
`(4.3%) or the type 3 neovascularization group (2.9%). When
`all three groups were analyzed together, submacular hem-
`orrhage was the second most common reason for exclusion.
`However, when each subtype was analyzed separately, the
`results changed. In the typical neovascular AMD and type 3
`neovascularization groups, only a small proportion of eyes
`was excluded by the subretinal hemorrhage criterion.
`(e present study may provide some useful information
`when planning a clinical trial for drug development. First,
`the study provides the number and proportion of patients
`who can be candidates for a clinical trial from among the
`entire real-world patient population. Although several fac-
`tors, such as informed consent or detailed systemic con-
`ditions, could not be evaluated, our data can be used to
`obtain a rough estimate of how many patients can be en-
`rolled in a clinical trial. Second, our study shows which parts
`of the eligibility criteria should be modified to facilitate
`patient enrollment. For example, patient enrollment can be
`facilitated by broadening the range of visual acuity. In a PCV
`study, including some hemorrhage cases by modifying the
`eligibility criterion regarding hemorrhage may be helpful in
`accelerating patient enrollment.
`Each clinical trial has its own inclusion and exclusion
`criteria. (us, treatment outcomes in a certain condition
`that does not meet the eligibility criteria cannot be fully
`evaluated through the trial. In such cases, subsequent studies
`are required to verify it. (e results of the present study may
`
`also provide useful information when planning these sub-
`sequent studies. For instance, 18.6% of patients can be
`potential candidates when planning a study on patients with
`initial visual acuity better than 20/40. In addition, the
`proportion will be 9.2% when planning a study on patients
`with subretinal hemorrhage.
`In general, clinical trials are expensive [7, 8], and this is
`an important burden to the company or organization
`hosting the trial [18]. In addition, the increase in the cost of
`drug development may increase the price of the drug and
`eventually increase the socioeconomic burden. To prevent
`unexpected increase in the cost of undertaking clinical trials,
`it is important to select suitable institutions for the trials. If
`information such as the results presented in this study is
`available to many institutions worldwide and is easily ac-
`cessible to the public, it will be a great help to global
`pharmaceutical companies or research institutes to easily
`identify the characteristics of institutions located in various
`countries. As a result, such information will contribute to the
`selection of more suitable institutions for clinical trials. In
`future, the development of artificial
`intelligence-assisted
`prescreening of participants eligible for clinical trial [19] may
`help facilitate this process.
`To our knowledge, only two previous studies have in-
`vestigated the proportion of patients that do not meet the
`eligibility criteria of clinical trials on neovascular AMD
`[20, 21]. George et al. found that less than half of the real-
`world patients would have passed the angiographic eligibility
`criteria used in the MARINA (Minimally Classic/Occult
`Trial of the Anti-VEGF Antibody Ranibizumab in the
`Treatment of Neovascular AMD) and ANCHOR (Anti-
`VEGF Antibody for the Treatment of Predominantly Classic
`Choroidal Neovascularization in AMD) studies. [20] (e
`main reasons were “choroidal neovascularization [CNV]
`
`< 50% of the lesion” in 33%, “location of CNV (extrafoveal,
`juxtafoveal, or peripapillary)” in 23.1%, and “size> 12 disc
`areas and blood> 50%” in 2.3% [20]. In the study of Gilles
`
`et al. [21], among 646 eyes that were treated in real-world
`setting, 401 (62.1%) met the eligible criteria for MARINA
`study. A substantial number of eyes failed to satisfy the
`criteria due to good or poor visual acuity [21].
`Although the method of analysis was similar between the
`present study and the study by George et al., there were
`obvious differences between the two studies. First, the
`primary purpose of the study by George et al. was to de-
`termine the proportion of patients who may be eligible for
`treatment with ranibizumab [20], whereas the primary
`purpose of the present study was more focused on the
`clinical trials themselves. (erefore, more detailed evalua-
`tion of each eligibility criterion was performed in the present
`study. Second, the reason for ineligibility differed between
`the two studies. In the study by George et al., only a small
`proportion of patients was found to be ineligible because of
`the observation of blood [20], whereas it was a primary
`reason for exclusion in the present study. We believe this
`difference could be attributed to the ethnic differences be-
`tween the patient populations included in the two studies;
`accordingly, the proportion of PCV might be markedly
`higher in the present study on an Asian population.
`
`Exhibit 2061
`Page 06 of 08
`
`

`

`Journal of Ophthalmology
`
`7
`
`It is important to know whether the drug efficacy shown
`in clinical trials is also valid in real-world setting, especially
`in patients excluded from the trials. In general, the real-
`world outcomes are relatively comparable or slightly inferior
`to that reported in clinical trials [15, 22, 23]. Woo et al.
`reported 12-week visual outcomes of ranibizumab based on
`real-world, postmarketing surveillance study data [22]. In
`that study, the visual gain was 7.5 letters at 12 weeks in
`treatment-na¨ıve patients and this was comparable to that
`reported in previous clinical trials [2, 4, 5]. More recently,
`Eter et al. reported a 24-month real-world efficacy of afli-
`bercept [15]. In that study, 6.7 letters of visual improvement
`were noted at 24 months in patients who received regular
`treatment. Altaweel et al. evaluated treatment outcomes of
`
`comparison of age-related macular degeneration treatment
`trials (CATT) data [23]. Patients with this characteristic were
`excluded from early clinical trials for ranibizumab [2]. As a
`result, eyes with the blood showed similar outcomes when
`compared to eyes without the blood. Based on this finding,
`the authors concluded that eyes with neovascular AMD
`
`eyes with lesions composed of >50% blood, based on
`lesions composed of>50% blood can be managed clinically
`
`in a similar manner as those without it [23]. However, in
`some cases, somewhat different outcomes are noted in real-
`world patients. In the study of Jung et al. [24], vitrectomized
`eyes
`required more
`frequent
`injections
`than non-
`vitrectomized eyes, suggesting patients’ characteristics can
`influence the treatment outcomes. (ese results suggest that
`the drugs introduced based on the results of clinical trials can
`be prescribed to real-world patients, but with care.
`(is study has some limitations. (is was a retrospective
`study performed in a single center. (us, the included pa-
`tients may not be representative of the entire global pop-
`ulation. Moreover, not all
`the eligibility criteria were
`evaluated. In addition, all the included patients were Korean.
`(e subtypes of neovascular AMD differ among different
`ethnic groups. In particular, PCV is more prevalent in Asian
`populations than in Caucasian populations [9]. (us, the
`results of the present study may not be valid in other ethnic
`groups. Since the eligibility criteria of the VIEW studies were
`used, the result may change when using the eligibility criteria
`of different studies. Visual acuities wer