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The future of decentralized clinical trials in ophthalmology

Digital EditionOphthalmology Times: December 2023
Volume 48
Issue 12

Research can drive opportunities for patients with rare diseases

(Image Credit: AdobeStock)

(Image Credit: AdobeStock)

In decentralized clinical trials (DCTs), investigators reduce dependence on intermediary specialists and traditional facilities for data acquisition by using virtual elements to facilitate treatment and data collection in a subject’s home.1 As clinical trials shift toward a more decentralized model, telemedicine is poised to play a more substantial role.

Telemedicine is one of many means by which DCTs can occur, and it uses technology to bridge distance between health care participants.2 In 2021, 29% of ophthalmology trials were fully decentralized or remote, with ophthalmology having the greatest percentage of full DCTs among all therapeutic areas.3

In 2023, a survey of staff working at clinical trial sites encompassing all therapeutic areas found that 92.7% of respondents expect
to facilitate full or partial DCTs in the next 12 months, which is an increase from 87.3% in 2022.4 This pattern is likely a by-product of the COVID-19 pandemic. In addition to being preferred by many participants, it also may enhance accuracy of some studies by reducing selection bias through the inclusion of historically disadvantaged and underrepresented individuals, such as those in rural areas, with low vision, or without reliable transportation.

Further, it can create opportunities for the inclusion of individuals with rare diseases.5 Findings from a recent survey of participants in oncology trials suggest that the opportunity to enroll in a DCT modality may result in greater willingness to consent.6 If the FDA’s recent draft guidance for DCTs is implemented, it is possible that any ophthalmology practice that is close to ophthalmology clinical trial participants could facilitate trial-
related activities and visits, even though the ophthalmology staff and providers may not formally be part of the trial personnel.7

Investigators have long remotely collected patient-reported outcomes data outside of the laboratory. One recent example is a study by Call et al, in which investigators utilized participants’ cell phones to collect real-time contact lens comfort data over 1 month of wear.8 Also, Greenan et al evaluated participants with primary Sjögren syndrome, and found that validated surveys such as the Vision Related Quality of Life and Health Related Quality of Life questionnaires are likely an effective adjunct to in-person consultations.9 These studies support the notion that investigators can remotely employ surveys in clinical trials where patient-reported outcomes are of interest.

Researchers have repeatedly demonstrated through numerous approaches that telemedicine can be an effective method of measuring visual acuity.10-15 For instance, Raffa et al found that smartphones have a 89.3% sensitivity of detecting abnormal visual acuity in pediatric subjects.10

Additionally, Ritchie et al found that at-home computer visual acuity testing is comparable to in-office testing.11 Karampatakis et al determined that a smartphone app is comparable to an in-office Early Treatment Diabetic Retinopathy Study (EDTRS) visual acuity test.12 Labiris et al determined that smart TV–based acuity testing is comparable (not inferior) to conventional ETDRS testing.13

Allen et al studied children aged 4 to 10 years and found that medical web application distance visual acuity testing is comparable to clinical testing.14 Lastly, Iskander et al tested near visual acuity on Android and iPhone users and discovered that the results correspond well with acuity taken with the Rosenbaum near visual acuity card.15 These studies’ results support the notion that, once validated in the home setting, remote visual acuity measurement may be able to carry over into many clinical trials where visual acuity is an outcome measure, such as studies involving clinically significant macular edema, age-related macular degeneration, amblyopia, and medical devices such as IOLs and intravitreal implants.

Although one might be concerned with the validity of more complex data collected through DCTs, results of a recent study suggest that ophthalmology nursing staff can accurately gather data on IOP, auto-refraction, keratometry, and visual acuity.16 This suggests that an ophthalmologist does not necessarily need to be there physically with the subject and that they could review test results remotely. This also specifically implies that investigators can employ telemedicine to accurately capture postoperative refractive data for refractive surgery and IOL trials.

Additionally, through telemedicine IOP measurement, investigators could screen for elevated IOP during glaucoma surgical trials. Thus, investigators will lose fewer participants to follow-up, and investigators can include greater diversity in trial samples, all with fewer visits to the research facility.

Clinical trials involving the management of fundus pathologies, such as clinically significant macular edema and age-related macular degeneration, can also benefit from decentralized imaging. Researchers demonstrated that smartphones and handheld cameras are comparable to tabletop cameras for screening diabetic retinopathy.17,18 In determining the presence of macular edema, de Oliveira et al found an 88.5% agreement between a handheld fundus camera and a tabletop fundus camera.17

Likewise, Midena et al found that a handheld fundus camera had a 96.9% sensitivity and 94.8% specificity for identifying any form of diabetic retinopathy.18 These instruments, therefore, can be employed to photograph the fundus during clinical trials that involve anti-VEGF therapeutics, intravitreal implants, and other treatments of fundus pathology. Further, portable optical coherence tomography (OCT) is showing promise as a future method of capturing more detailed retinal images in studies and trials. These tools are already capable of imaging clinically significant macular edema.19

Notal Vision is developing a home-based OCT geared toward patients with wet age-related macular degeneration. This could be a valuable adjunct for remote assessment of anti-VEGF therapy.20 In the case of DCT imaging, given the high equipment value and the training required to accurately perform the testing, clinical staff would likely need to send or contract trial staff to participants’ homes.

Glaucoma trials may also benefit from telemedicine. Patient-administered tonometry measurements have consistently been shown to be similar to Goldmann Applanation Tonometer measurements, suggesting that patient-administered IOP measurements may be a feasible option for assessing ocular hypotensive and surgical intervention efficacies.21 Further, investigators previously demonstrated that remote optic disc imaging effectively identifies patients with optic disc cupping, which could prove helpful in assessing cup-to-disc ratios in patients with glaucoma who are enrolled in clinical trials.22

If home-based OCT is on the forefront, it is only a matter of time before retinal nerve fiber layer and ganglion cell layer thickness can be remotely assessed through artificial intelligence and established algorithms, thus reducing the need for participants to travel to a data collection site. Remotely measured visual fields, alternatively, demonstrated a positive correlation to visual field testing on the Humphrey perimeter, suggesting decentralized visual field testing can potentially monitor visual fields in glaucoma trials.23,24

Investigators facilitating clinical trials of ocular surface disease or trials that involve anterior segment pathology can also employ telemedicine for decentralized data collection. For example, investigators found that participant self-imaging via an electronic device was consistent with in-office slit lamp photography.25 Of course, this may not be a solution for all participants, as self-imaging may be challenging or impossible for those with poor dexterity, low vision, or unfamiliarity with modern technology.

Further, areas of interest or pathology may be missed or out of focus if an examiner is not viewing the images in real time and guiding the participant. Still, the fact that this technology exists and has shown efficacy opens the door to postoperative assessment in medical device trials and therapeutics that treat patients with ocular surface disease.

Although additional work is needed before DCTs will be fully accepted by the community, they have the potential to lower costs, improve participant experience, reduce the number of participant lost to follow-up, enhance diversity, save time, and improve clinical trial results.4 These potential benefits are impossible to ignore, and when paired with the validation of remote ophthalmologic testing, investigators will likely accept this innovative approach to clinical trials.However, we cannot expect this transition to occur overnight.

The ophthalmology community will need to settle on which procedures are the most accurate and meaningful and then validate them. Additionally, the FDA will also need to analyze and incorporate comment submissions regarding their recent draft DCT guidance into unequivocal guidance that investigators can follow. Once these events occur, we can expect a new era in ophthalmology clinical trials.

EDITOR’S NOTE: The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Department of the Army, the US Department of Defense, or the US government.
George Magrath, MD
E: magrath@musc.edu
Magrath is CEO of Lexitas Pharma Services Inc. He is a trained ocular oncologist, balancing his role as CEO with treating patients with rare eye conditions at the Medical University of South Carolina in Charleston. While learning his craft with an internship in general surgery, a residency in ophthalmology at the Medical University of South Carolina, and a fellowship in ocular oncology at Wills Eye Hospital in Philadelphia, Pennsylvania, he branched out into the business world with a master’s degree in business administrationfrom The Citadel in Charleston and a master’s degree in applied economics from Johns Hopkins University in Baltimore, Maryland.
Andrew Pucker, OD, PhD, FAAO, FSLS, FBCLA
P: 614-292-2020
Pucker is director of clinical and medical sciences at Lexitas Pharma Services. He earned his OD, PhD, and MSdegrees from The Ohio State University in Columbus, and he is the former director of the UAB Eye Care Myopia Control Clinic. He has received research or consulting support from Alcon Research Ltd, Art Optical, and Haymarket Media Group in the past year.
Winston Posvar, OD, MS
E: winston.b.posvar.mil@mail.mil
Posvar is a clinician, health care administrator, and a major in the US Army. He currently is conducting a clinical and medical sciences research project at Lexitas Pharma Services. The views expressed in this article are those of the author and do not reflect the official policy or position of the US Department of the Army, the US Department of Defense, or the US government.
1. Van Norman GA. Decentralized clinical trial: the future of medical product development? JACC Basic Transl Sci. 2021;6(4):384-387. doi:10.1016/j.jacbts.2021.01.011 doi: 10.1016/j.jacbts.2021.01.011
2. Institute of Medicine (US) Committee on Evaluating Clinical Applications of Telemedicine; Field MJ, ed. Introduction and Background. In: Telemedicine: A Guide to Assessing Telecommunications in Health Care. National Academies Press (US); 1996. Accessed June 5, 2023. https://www.ncbi.nlm.nih.gov/books/NBK45440/ doi: 10.17226/5296
3. 2022 fecentralized clinical trials survey. PPD. Accessed June 5, 2023. https://www.ppd.com/how-we-help/decentralized-clinical-trials/dcts-sites-survey/ doi: 10.1007/s43441-023-00540-2
4. Decentralized clinical trials sites survey. 2023. Accessed June 5, 2023. https://www.ppd.com/wp-content/uploads/2023/03/PPD238_SurveyReport2023_F.pdf doi: 10.1007/s43441-023-00540-3
5. Ghadessi M, Di J, Wang C, et al. Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective. Orphanet J Rare Dis. 2023;18(1):79. doi: 10.1186/s13023-023-02693-7
6. Adams DV, Long S, Fleury ME. Association of remote technology use and other decentralization tools with patient likelihood to enroll in cancer clinical trials. JAMA Netw Open. 2022;5(7):e2220053. doi: 10.1001/jamanetworkopen.2022.20053
7. Decentralized clinical trials for drugs, biological products, and devices: guidance for industry, investigators, and other stakeholders. FDA. May 2023. Accessed June 5, 2023. https://www.fda.gov/media/167696/download
8. Call T, Pucker AD, McGwin G Jr, Franklin QX, Logan A. Real-time ocular comfort reporting in monthly replacement contact lens wearers. Clin Optom (Auckl). 2023;15:97-103. doi:10.2147/OPTO.S403319
9. Greenan E, Pilson Q, Ní Gabhann-Dromgoole J, Murphy CC. Quality of life questionnaires validate a remote approach to ophthalmic management of primary Sjögren’s syndrome. Sci Rep. 2022;12(1):18761.
10. Raffa LH, Balbaid NT, Ageel MM. “Smart Optometry” phone-based application as a visual acuity testing tool among pediatric population. Saudi Med J. 2022;43(8):946-953.doi: 10.1038/s41598-022-23676-x
11. Ritchie A, Atamian S, Shah N, Laidlaw A, Hammond C. Can visual acuity be reliably measured at home? validation of telemedicine remote computerised visual acuity measurements. Br Ir Orthopt J. 2021;17(1):119-126. doi: 10.22599/bioj.179
12. Karampatakis V, Almaliotis D, Talimtzi P, Almpanidou S. Design and validation of a novel smartphone-based visual acuity test: the K-VA test. Ophthalmol Ther. 2023;12(3):1657-1670. doi: 10.1007/s40123-023-00697-x
13. Labiris G, Delibasis K, Panagiotopoulou EK, et al. Development and validation of the first smart TV-based visual acuity test: a prospective study. Healthcare (Basel). 2022;10(11):2117.
14. Allen L, Thirunavukarasu AJ, Podgorski S, Mullinger D. Novel web application for self-assessment of distance visual acuity to support remote consultation: a real-world validation study in children. BMJ Open Ophthalmol. 2021;6(1):e000801. doi: 10.3390/healthcare10112117
15. Iskander M, Hu G, Sood S, et al. Validation of the New York University Langone Eye Test application, a smartphone-based visual acuity test. Ophthalmol Sci. 2022;2(3):100182.doi: 10.1016/j.xops.2022.100182
16. Garcia Moraes Pagano C, de Campos Moreira T, Sganzerla D, et al. Teaming-up nurses with ophthalmologists to expand the reach of eye care in a middle-income country: validation of health data acquisition by nursing staff in a telemedicine strategy. PloS One. 2021;16(11):e0260594.doi: 10.1371/journal.pone.0260594
17. de Oliveira JAE, Nakayama LF, Zago Ribeiro L, et al. Clinical validation of a smartphone-based retinal camera for diabetic retinopathy screening. Acta Diabetol. 2023;60(8):1075-1081. doi:10.1007/s00592-023-02105-z
18. Midena E, Zennaro L, Lapo C, et al. Handheld fundus camera for diabetic retinopathy screening: a comparison study with table-top fundus camera in real-life setting. J Clin Med. 2022;11(9):2352.
19. Chopra R, Wagner SK, Keane PA. Optical coherence tomography in the 2020s—outside the eye clinic. Eye (Lond). 2021;35(1):236-243. doi: 10.3390/jcm11092352
20. Harp MD. Notal Vision shares data on novel home OCT device. Ophthalmology Times. February 25, 2023. Accessed May 19, 2023. https://www.ophthalmologytimes.com/view/notal-vision-shares-data-on-novel-home-oct-device
21. Liu J, De Francesco T, Schlenker M, Ahmed II. Icare home tonometer: a review of characteristics and clinical utility. Clin Ophthalmol. 2020;14:4031-4045. 22. Cheng D, Babij R, Cabrera D, et al. Effective low-cost ophthalmological screening with a novel iPhone fundus camera at community centers. Cureus. 2022;14(8):e28121. doi: 10.2147/OPTH.S284844
23. Tsapakis S, Papaconstantinou D, Diagourtas A, et al. Home-based visual field test for glaucoma screening comparison with Humphrey perimeter. Clin Ophthalmol. 2018;12:2597-2606.doi: 10.2147/OPTH.S187832
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25. van der Star L, Mulders-Al-Saady R, Phan A, et al. First clinical experience with ophthalmic e-device for unaided patient self-examination during COVID-19 lockdown. Cornea. 2022;41(3):353-358.doi: 10.1097/ICO.0000000000002945
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