Evolving Clinical Practice: Insights Gained from Real-World Evidence

Authors: Robert P. Finger¹, Taiji Sakamoto², James Talks³, Vincent Daien^4,5, Tien Wong^6,7, Bora Eldem⁸, Paul Mitchell⁹,Jean-François Korobelnik^10,11

1. - Department of Ophthalmology, University of Bonn, Bonn, Germany

2. - Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, and J-CREST, Japan

3. - Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

4. - Department of Ophthalmology, Gui De Chauliac Hospital, Montpellier, France

5. - The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia

6. - Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

7.- Duke-NUS Medical School, Singapore, Singapore

8. - Faculty of Medicine, Ophthalmology Department, Hacettepe University, Ankara, Turkey

9. - Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, NSW, Australia

10. - CHU Bordeaux, Service d'ophtalmologie, Bordeaux France

11. - Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, F-33000 Bordeaux, France

Disclosures:

R. P. Finger – Consulting/paid presentations for Bayer, Novartis, Roche/Genentech, Novelion, Opthea, Inositec, Santhera Alimera and Ellex; Research for Novartis, Zeiss, and CentreVue; T. Sakamoto – Alcon, Bayer, Novartis, Santen, Senju and Wakamoto; J. S. Talks – Advisory boards for Bayer; Novartis and Allergan; Research for Bayer, Novartis, Allergan and Roche; Travel sponsorships for Bayer and Novartis; V. Daien – Alcon, Bayer, Horus, Novartis and Thea; T. Y. Wong – Abbott, Allergan, Bayer, Novartis, Pfizer and Roche; B. M. Eldem – Consultant to Bayer, Novartis, Allergan and Investigator to Roche; P. Mitchell – Consultant for Bayer, Novartis, Allergan, Roche and Abbott; J.-F. Korobelnik – Alcon, Allergan, Bayer, Beaver Visitec, Horus, Krys, Kanghong, NanoRetina, Novartis, Roche, Thea and Zeiss

The authors have no commercial interests in relation to the article. Medical writing and editorial support for preparation of the article, under the guidance of the authors, was provided by ApotheCom, which was funded by Bayer Consumer Health.

Real-world evidence (RWE) is generated during routine clinical practice, outside the restricted environment of randomised controlled trials (RCTs). There is a growing focus on RWE, as it enables healthcare professionals, pharmaceutical companies and decision-makers to build on knowledge from RCTs. In this way, the influence of RWE on the management of retinal disease in clinical practice is growing rapidly, as it plays an increasingly important role in regulatory and clinical decision-making.

What is the difference between RWD and RWE?

As defined by the US Food and Drug Administration (FDA):¹

How does RWE supplement RCT data?

RCTs provide evidence for the efficacy of a treatment based on testing in a selected population, under rigorous and tightly controlled conditions, over relatively short periods of time.² By contrast, RWE is typically based on data from routine clinical practice and provides detail on the effectiveness, safety and utilisation of a treatment under real-world conditions, often with diverse patient populations.^3-5

Both data from RCTs and real-world studies are important when evaluating new interventions, and each source provides data serving different purposes. Real-world studies complement findings from RCTs by examining interventions under conditions that closely reflect the heterogeneous patient populations, and less-standardised treatment protocols associated with clinical practice.³ This means RWE can often be better generalised to typical clinical practice than evidence from RCTs (Figure 1).

As well as generating effectiveness data, real-world studies are also able to generate information on other topics of interest. These may include variation in practice patterns, patient-related outcomes, such as quality of life, cost-benefit, and the influence of varied patient characteristics on outcomes. In this way, RWE can be used to help service provision improvement, and to support reimbursement and monitoring decisions.³

Sources of RWD

RWD can be collected prospectively for a specific research purpose (known as primary RWD), or retrospectively from a range of different sources that contain data collected for other purposes (known as secondary RWD), usually non-research related.³

The role of RWE in informing the management of retinal disease

In retinal disease, real-world studies evaluating the management of neovascular age-related macular degeneration (nAMD) have informed dosing strategies with anti-VEGFs in clinical practice.

• Both aflibercept and ranibizumab were initially approved for the treatment of nAMD in fixed dosing regimens following results from phase 3 RCTs (VIEW 1&2 for aflibercept, and MARINA and ANCHOR for ranibizumab)^8-10
• Several subsequent real-world studies have reinforced the findings from these RCTs
  • For example, the PERSEUS and RAINBOW studies evaluated the effectiveness of aflibercept treatment in treatment naïve patients with nAMD in routine clinical practice,^11,12 with similar visual outcomes observed with regular aflibercept treatment to those in the VIEW RCTs, at Month 128
• However, other real-world studies have shown that visual outcomes achieved with anti-vascular endothelial growth factor (VEGF) in clinical practice sometimes differ from those derived from RCTs
  • For example, the LUMINOUS study evaluated real-world ranibizumab use in treatment naïve patients with nAMD,¹³ with markedly lower changes in visual acuity observed over the first year of treatment, compared with those in the MARINA and ANCHOR RCTs^9,10
• These disparities may be partially explained by anti-VEGF use in practice differing from the strict regimens used in RCTs, often in an attempt to reduce treatment burden associated with intravitreal injections.
  • For example, 69–76% of patients in the PERSEUS, RAINBOW and LUMINOUS studies were not treated with regular fixed treatment
  • In both PERSEUS and RAINBOW, regular treatment with aflibercept was associated with greater improvements in visual acuity, compared with an irregular treatment regimen^{11, 13} Similar observations were observed in the LUMINOUS study, in which patients who received fewer injections of ranibizumab experienced smaller gains in visual acuity than those who received more frequent injections¹⁴
  • Collectively, these data suggest that despite the original anti-VEGF labels indicating regular fixed dosing, in practice, treatment was largely given following different, irregular protocols in these studies. In addition, these irregularities in dosing and treatment strategies in clinical practice are associated with worse outcomes than with regular dosing, supporting the need for regular proactive treatment
• Recently, further efforts have been made to optimise anti-VEGF dosing strategies in clinical practice to meet individual patients’ needs, optimise visual outcomes and reduce treatment burden. For example, there is a growing body of evidence from real-world studies, to support the use of treat-and-extend dosing of anti-VEGF agents as a way of optimising visual outcomes whilst minimising injection frequency.^15-17 With treat-and-extend dosing, the interval between anti-VEGF injections is gradually extended until fluid recurs, or visual acuity falls. The patient is then injected more frequently than their maximal fluid-free interval to maintain vision, whilst minimising injection frequency.¹⁸
• RWE has also provided useful information regarding the time to reactivation of nAMD when anti-VEGF treatment is discontinued. For example, the analysis of large data sets in the FRB! Registry confirmed a high rate of disease reactivation over time after disease stability was achieved, and anti-VEGF treatment ceased.¹⁹ This was subsequently confirmed by other large observational studies.²⁰ These and similar insights from RWE, which are not gained from RCTs, could inform future guideline recommendations for the management of retinal disease. These could include more specific recommendations on patient follow-up after treatment discontinuation, risk and management of systemic and ocular adverse events, and management of patients with higher baseline visual acuity than those in RCTs or bilateral disease.

Summary

RWE provides information on the effectiveness of a treatment under real-world conditions and is increasingly recognised as an important tool for informing clinical decision-making. In retinal disease, RWE is particularly important as it can help to continually assess real-world treatment regimens in order to improve patient outcomes and reduce treatment burden. For example, RWE has helped to guide treatment strategies in nAMD, with evidence suggesting that regular proactive treatment is most likely to sufficiently balance clinical outcomes and treatment burden for patients with nAMD.^11-17

References

1. Administration UFaD. Framework for FDA’s Real-World Evidence Program. Available at: https://www.fda.gov/media/120060/download.

2. Garrison LP, Jr., Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5):326-335.

3. Talks J. Utility of real-world evidence for evaluating anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration. Survey of Ophthalmology. 2018;In press.

4. Food and Drug Administration. Framework for FDA's real-world evidence program. Available at: https://www.fda.gov/media/120060/download.

5. Berger M, Daniel G, Frank K, et al. White paper: A framework for regulatory use of real-world evidence. 2017.

6. Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16:495.

7. Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS clinical trials. 2006;1(1):e9.

8. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.

9. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. The New England Journal of Medicine. 2006;355(14):1419-1431.

10. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65.e55.

11. Framme C, Eter N, Hamacher T, et al. Aflibercept for Patients with Neovascular Age-Related Macular Degeneration in Routine Clinical Practice in Germany. Ophthalmology Retina. 2018;2(6):539-549.

12. Weber M, Velasque L, Coscas F, Faure C, Aubry I, Cohen ANobotRsi. Effectiveness and safety of intravitreal aflibercept in patients with wet age-related macular degeneration treated in routine clinical practices across France: 12-month outcomes of the RAINBOW study. BMJ Open Ophthalmology. 2019;Accepted.

13. Faure C, Cohen S-Y, Coscas F, et al. Real-world effectiveness and safety of intravitreal aflibercept regimens in patients with wet age-related macular degeneration: updated 12-month outcomes of RAINBOW. The 9th Annual Congress on Controver sies in Ophthalmology: Europe (COPHy EU); March 22-24, 2018, 2018; Athens, Greece.

14. Souied E, Clemens A, Macfadden W. Ranibizumab in patients with neovascular age-related macular degeneration: results from the real-world LUMINOUS™ study. Acta Ophthalmol. 2017;https://doi.org/10.1111/j.1755-3768.2017.01111.

15. Lee AY, Lee CS, Egan CA, et al. UK AMD/DR EMR REPORT IX: comparative effectiveness of predominantly as needed (PRN) ranibizumab versus continuous aflibercept in UK clinical practice. Br J Ophthalmol. 2017;101(12):1683-1688.

16. Epstein D, Amren U. Near Vision Outcome in Patients with Age-Related Macular Degeneration Treated with Aflibercept. Retina. 2016;36(9):1773-1777.

17. Hanemoto T, Hikichi Y, Kikuchi N, Kozawa T. The impact of different anti-vascular endothelial growth factor treatment regimens on reducing burden for caregivers and patients with wet age-related macular degeneration in a single-center real-world Japanese setting. PLoS One. 2017;12(12):e0189035.

18. Lanzetta P, Loewenstein A, Vision Academy Steering C. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255(7):1259-1273.

19. Essex RW, Nguyen V, Walton R, et al. Treatment Patterns and Visual Outcomes during the Maintenance Phase of Treat-and-Extend Therapy for Age-Related Macular Degeneration. Ophthalmology. 2016;123(11):2393-2400.

20. Mehta H, Tufail A, Daien A, et al. Real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors. Progress in retinal and eye research. 2018;65:127-146.

21. Talks JS, James P, Sivaprasad S, Johnston RL, McKibbin M, Group UKAU. Appropriateness of quality standards for meaning ful intercentre comparisons of aflibercept service provision for neovascular age-related macular degeneration. Eye (Lond). 2017;31(11):1613-1620.

22. Holz FG, Tadayoni R, Beatty S, et al. Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study. Eye (Lond). 2016;30(8):1063-1071.

Eylea Prescribing information

Name of the medicinal product: Eylea 40 mg/ml solution for injection. (Refer to full SmPC before prescribing.) Composition Each vial contains 100 μl, equivalent to 4 mg aflibercept. Excipients: Polysorbate 20, Sodium dihydrogen phosphate, monohydrate, Disodium hydrogen phosphate, heptahydrate, Sodium chloride, Sucrose, Water for injection.

Indication: Eylea is indicated for adults for treatment of neovascular (wet) age-related macular degeneration (AMD), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular oedema (DME) and visual impairment due to myopic choroidal neovascularisation (myopic CNV).

Administration and Dosage: For intravitreal injection only. Each vial should only be used for the treatment of a single eye. Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection. Administration only by qualified physician experienced in administering intravitreal injections. Recommended dose: 2 mg aflibercept (0.05 ml) equivalent to 50 microlitres. For wet AMD, treatment is initiated with 1 injection per month for 3 consecutive doses. The treatment interval is then extended to 2 months. Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be maintained at 2 months or further extended using a treat-and-extend dosing regimen, where injection intervals are increased in 2- or 4-weekly increments to maintain stable visual and/or anatomic outcomes. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly to a minimum of 2 months during the first 12 months of treatment. There is no requirement for monitoring between injections. Based on the physician’s judgement the schedule of monitoring visits may be more frequent than the injection visits. Treatment intervals greater than 4 months between injections have not been studied. For RVO (branch RVO or central RVO), after initial injection, treatment is given monthly. The interval between the 2 doses should not be shorter than 1 month. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued. Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed. Treatment may then be continued with a treat-and-extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes; however, there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). For DME, initiate treatment with 1 injection/month for 5 consecutive doses, followed by 1 injection every 2 months. No requirement for monitoring between injections. After the first 12 months of treatment, and based on visual and/or anatomic outcomes, the treatment interval may be extended such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however, there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. For myopic CNV, a single injection is to be administered. Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease. The schedule for monitoring should be determined by the treating physician. The interval between 2 doses should not be shorter than 1 month.

Contraindications:

Hypersensitivity to aflibercept or to any of the excipients. Active or suspected ocular or periocular infection. Active severe intraocular inflammation.

Warnings and Precautions:

Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Aseptic injection technique is essential. Additionally, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients must report any symptoms of endophthalmitis or any of the above-mentioned events without delay. Increases in intraocular pressure (IOP) were seen within 60 min. of intravitreal injection. Special precaution is needed in poorly controlled glaucoma (no injection while IOP is ≥ 30 mmHg). In all cases, IOP and perfusion of optic nerve head must be monitored and managed appropriately. Potential for immunogenicity. Instruct patients to report any signs or symptoms of intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systematically studied. No data are available on the concomitant use of Eylea with other anti-VEGF medicinal products (systemic or ocular). Risk factors associated with development of retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include large and/or high pigment epithelial retinal detachment. When initiating therapy, use caution in patients with these risk factors for retinal pigment epithelial tears. Withhold treatment in patients with rhegmatogenous retinal detachment or stage 3 or 4 macular holes. Withhold dose and treatment should not be resumed in event of a retinal break until break is adequately repaired. Withhold dose and do not resume treatment earlier than next scheduled treatment in event of: decrease in best-corrected visual acuity of ≥ 30 letters compared with last assessment; subretinal haemorrhage involving centre of fovea, or, if size of haemorrhage is ≥50%, of total lesion area. Withhold dose within previous or next 28 days in event of performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept. Populations with limited data: There is limited experience with treatment of patients with ischaemic CRVO and BRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended. There is limited experience in DME due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

Undesirable effects:

Very common: Visual acuity reduced, conjunctival haemorrhage, eye pain. Common: Retinal pigment epithelial tear (known to be associated with wet AMD; observed in wet AMD studies only), detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract, cataract cortical, cataract nuclear, cataract subcapsular, corneal erosion, corneal abrasion, intraocular pressure increased, vision blurred, vitreous floaters, vitreous detachment, injection-site pain, foreign body sensation in eyes, lacrimation increased, eyelid oedema, injection-site haemorrhage, punctate keratitis, conjunctival hyperaemia, ocular hyperaemia. Uncommon: Hypersensitivity (during the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions), culture positive and culture negative endophthalmitis, retinal detachment, retinal tear, iritis, uveitis, iridocyclitis, lenticular opacities, corneal epithelium defect, injection-site irritation, abnormal sensation in eye, eyelid irritation, anterior chamber flare, corneal oedema. Rare: Blindness, cataract traumatic, vitritis, hypopyon. Description of selected adverse reactions: In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage in patients receiving anti-thrombotic agents. Arterial thromboembolic events are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. As with all therapeutic proteins, there is a potential for immunogenicity.

On prescription only. Marketing Authorisation Holder: Bayer AG, 51368 Leverkusen, Germany.

Date of revision of the underlying Prescribing Information: July 2018.