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New and emerging health technologies for corneal disorders

Horizon Scanning Research & Intelligence Centre

September 2016

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About the National Institute for Health Research (NIHR) Horizon Scanning Research & Intelligence Centre (HSRIC) The NIHR HSRIC is based at the University of Birmingham in the UK. The centre aims to supply timely information to key health policy and decision-makers and research funders within the NHS about emerging health technologies that may have a significant impact on patients or the provision of health services in the near future. The scope of our activity includes pharmaceuticals, medical devices and equipment, diagnostic and screening tests, interventional procedures, therapeutic interventions, rehabilitation and therapy, and public health activities.

NIHR HSRIC reports can be accessed free of charge via our website at: www.hsric.nihr.ac.uk The centre can be followed on Twitter at: @OfficialNHSC

This report presents independent research funded by the National Institute for Health Research. The views expressed in this publication are those of the authors

and not necessarily those of the NIHR, NHS, or the Department of Health

The NIHR Horizon Scanning Research & Intelligence Centre University of Birmingham, United Kingdom

nihrhsric@contacts.bham.ac.uk www.hsric.nihr.ac.uk

Copyright © University of Birmingham 2016

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CONTENTS

EXECUTIVE SUMMARY ...................................................................................................... 5

ACKNOWLEDGEMENTS ..................................................................................................... 6

1 INTRODUCTION ...................................................................................................... 7

1.1. CLINICAL NEED AND BURDEN OF DISEASE .............................................................................. 7

1.2. CURRENT TREATMENT .......................................................................................................... 9 1.2.1. ABRASION, EROSION OR SURFACE IRREGULARITES ........................................................... 9 1.2.2. ASTIGMATISM ..................................................................................................................... 9 1.2.3. INFECTIOUS KERATITIS ...................................................................................................... 10 1.2.4. INFLAMMATION ................................................................................................................ 10 1.2.5. LIMBAL STEM CELL DEFICIENCY ........................................................................................ 10 1.2.6. OEDEMA ............................................................................................................................ 11 1.2.7. OPACITY............................................................................................................................. 11 1.2.8. PERFORATION ................................................................................................................... 11 1.2.9. THINNING .......................................................................................................................... 11 1.2.10. TRANSPLANT REJECTION ................................................................................................... 11 1.2.11. ULCERATION ...................................................................................................................... 12

2 AIMS .................................................................................................................... 12

3 METHODS ............................................................................................................ 12

3.1. IDENTIFICATION ................................................................................................................... 12 3.1.1. ELECTRONIC IDENTIFICATION SOURCES ........................................................................... 12 3.1.2. OTHER IDENTIFICATION SOURCES .................................................................................... 12

3.2. INVESTIGATION AND FILTRATION ......................................................................................... 13

3.3. ASSESSMENT OF IMPACT ..................................................................................................... 14 3.3.1. PATIENT FOCUS GROUPS .................................................................................................. 14 3.3.2. EXPERT ADVISORY GROUP ................................................................................................ 14

4 RESULTS ............................................................................................................... 16

4.1. TECHNOLOGIES BY INDICATION ............................................................................................ 17 4.1.1. ABRASION, EROSION OR SURFACE IRREGULARITIES ........................................................ 19 4.1.2. ASTIGMATISM ................................................................................................................... 19 4.1.3. BURNS ............................................................................................................................... 20 4.1.4. CORNEA DISORDER (NOT OTHERWISE SPECIFIED) ........................................................... 20 4.1.5. CYSTINOSIS ........................................................................................................................ 20 4.1.6. ENDOTHELIAL DISEASE ...................................................................................................... 20 4.1.7. EPITHELIAL INCLUSION CYST ............................................................................................. 21 4.1.8. GRAFT REJECTION ............................................................................................................ 21 4.1.9. INFECTION ......................................................................................................................... 21

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4.1.10. INFLAMMATION ................................................................................................................ 21 4.1.11. KERATOCONJUCTIVAL DISEASE, INTRACTABLE ................................................................. 21 4.1.12. NEOPLASIA ........................................................................................................................ 22 4.1.13. NERVE DISORDER .............................................................................................................. 22 4.1.14. OEDEMA ............................................................................................................................ 22 4.1.15. OPACITY............................................................................................................................. 22 4.1.16. PAIN ................................................................................................................................... 22 4.1.17. PERFORATION ................................................................................................................... 23 4.1.18. PTERYGIUM ....................................................................................................................... 23 4.1.19. STEM CELL DEFICIENCY ..................................................................................................... 23 4.1.20. THINNING .......................................................................................................................... 23 4.1.21. ULCER ................................................................................................................................ 24

4.2. TECHNOLOGIES BY TYPE ....................................................................................................... 24 4.2.1. BIOLOGICAL AND CELLULAR THERAPIES ........................................................................... 25 4.2.2. DEVICES ............................................................................................................................. 26 4.2.3. DRUGS ............................................................................................................................... 26 4.2.4. PROCEDURES ..................................................................................................................... 26

4.3. GENERAL COMMENTS ON NEW AND EMERGING TECHNOLOGIES .......................................... 27 4.3.1. PATIENT COMMENTS ........................................................................................................ 27 4.3.2. EXPERT COMMENTS .......................................................................................................... 27

5 DISCUSSION ......................................................................................................... 28

6 CONCLUSION ........................................................................................................ 29

7 APPENDICES ......................................................................................................... 30 APPENDIX 1. EXPERT ADVISORY GROUP .......................................................................................... 30 APPENDIX 2. ELECTRONIC SOURCES OF INTELLIGENCE USED TO IDENTIFY TECHNOLOGIES .......... 31 APPENDIX 3. SEARCH TERMS USED .................................................................................................. 33 APPENDIX 4. LAYERS OF THE CORNEA .............................................................................................. 34 APPENDIX 5A. NUMBER OF DEVELOPMENTS BY TYPE AND INDICATION GROUP .............................. 35 APPENDIX 5B. DEVELOPMENTS (DESCRIPTION & FURTHER INFORMATION) .................................... 39 APPENDIX 6. COMMENTS FROM FIGHT FOR SIGHT ....................................................................... 100

8 REFERENCES ....................................................................................................... 102

TABLES & FIGURES: TABLE 1: REVIEW INCLUSION AND EXCLUSION CRITERIA ............................................................... 13 TABLE 2: IDENTIFIED TECHNOLOGIES AND PROCEDURES — BY INDICATION ................................ 17 TABLE 3: IDENTIFIED TECHNOLOGIES AND PROCEDURES — BY TYPE ............................................ 24 FIGURE 1: PRIMARY DIAGNOSIS OF RECIPIENTS OF DONOR CORNEAS 2015-2016 ............................... 8 FIGURE 2: NUMBER OF RECIPIENTS OF DONOR CORNEAS BY DIAGNOSIS IN 2000-2015 ...................... 8 FIGURE 3: HORIZON SCANNING REVIEW IDENTIFICATION AND FILTRATION FLOW DIAGRAM ........... 16 FIGURE 4: NUMBER OF TECHNOLOGIES BY TECHNOLOGY TYPE FOR EACH INDICATION GROUP. ...... 17

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EXECUTIVE SUMMARY

The National Institute for Health Research (NIHR) Horizon Scanning Research & Intelligence Centre (HSRIC) conducted a horizon scanning review of new and emerging treatments for disorders of the cornea. The review was carried out between February and July 2016, in collaboration with Fight for Sight, in response to a research question identified by the James Lind Alliance Priority Setting Partnership on Sight Loss and Vision (Corneal and External Eye Conditions). Corneal disorders such as corneal dystrophies, advanced keratoconus, keratitis and corneal neovascularisation can cause severe sight loss. The UK transplant registry recorded 3,789 donor corneal transplants in 2015-2016. Donor corneas for transplant are limited, and transplants require life-long immunosuppression, therefore other treatment options are needed. We searched a wide range of sources of intelligence for new and emerging technologies including: bibliographical databases; clinical trial registries; commercial pharmaceutical and medical technology databases; MedTech industry news sites; ophthalmology groups and networks; medical horizon scanning databases; professional conference proceedings; regulatory authorities; and research funding databases. We also asked clinical experts and patients to tell us about any technologies in development that they were aware of. Technology developers were contacted where more information was required on the identified technologies and a filtered list of technologies meeting our inclusion criteria was prepared. We engaged an expert group and Fight for Sight convened two patient focus groups to assess the impact of the technologies identified. One hundred and thirty technologies and procedures were identified; 28 cellular and biological therapies, 23 devices, 30 pharmaceuticals and 49 procedures. Most of the developments were in clinical research studies and many were in development outside of Europe. The experts stated that barriers existed to the adoption of cellular and biological therapies for the treatment of corneal disorders including cost, and noted a delay in the adoption of allogeneic therapy across Europe. The experts felt that endothelial cell therapies “will have a significant impact on the management of corneal endothelial failure globally”, particularly on the “current practice of endothelial keratoplasty, promising to deliver minimally invasive corneal/cell transplantation”. However, “the vast majority of the biological therapies listed were in development by academic organisations; the lack of a commercial partner suggesting that either the benefits are not established yet and/or that these therapies may try to reach the market through the hospital exemptions route (as the fully licensed route would be too expensive for such establishments)”. Artificial corneas were thought to be important, “innovative and creative” alternatives to corneal tissue and “an answer to hundreds of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection”. Scleral and osmotic contact lenses were deemed “useful”. The patient focus groups perceived that overall autologous cell therapies were the safest treatment, with no rejection, and that the treatment outcome could last longer. For them, the use of allogeneic tissue was a concern because of the need for life-long immunosuppressant. Generally, the focus groups preferred treatments with lower immediate and long term risk, so invasive procedures were seen as a last resort. Overall, both the clinical experts and the patients wanted to see more safety and efficacy studies. Also the patients wanted to know about the need for after care, and a treatments impact on recovery and long term benefits when compared with the standard of care.

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ACKNOWLEDGEMENTS

The NIHR HSRIC would like to thank the following for their contribution to the review: Expert Advisory Group • Mr Romesh I Angunawela, Consultant Eye Surgeon: Cornea, Cataract and Refractive Surgery,

Moorfields Eye Hospital and Honorary Senior Lecturer, UCL and St George's University of London.

• Dr Sajjad Ahmad, Senior Clinical Lecturer in Ocular Stem Cell Biology and Honorary Consultant Ophthalmologist, Royal Liverpool University Hospital, Liverpool.

• Mr Samer Hamada, Consultant Ophthalmic Surgeon: Cornea, Cataract, External Eye Disease, and Refractive Surgery in Children and Adults, Queen Victory Hospital, East Grinstead and The Wellington Hospital, London.

• Mr Panos Kefalas – Head of Health Economics and Market Access, Cell and Gene therapy Catapult, London.

Patient Involvement • Fight for Sight – Carol Bewick, Director of Policy and Communications, & Ade Deane-Pratt,

Research Communications Officer. • James Lind Alliance – Katherine Cowan, Senior Adviser and Patient Focus Group Facilitator. • Members of the patient focus groups. Other • NHS Blood and Transplant – UK Transplant Registry. • Medilink West Midlands – Jo Mewis, Service & Membership Manager.

NIHR HSRIC Review Team

• Tracey Genus, Analyst. • Dr Sue Simpson, Reviews Team Lead • Dr Derek Ward, Medical Advisor.

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1 INTRODUCTION

In 2012-13, the Sight Loss and Vision Priority Setting Partnership (PSP), comprising patients, carers and health care professionals, under the direction of The James Lind Alliance (JLA) identified and prioritised unanswered questions about the prevention, diagnosis and treatment of sight loss. One of the top ten questions about corneal and external eye conditions that arose was - Can new therapies such as gene or stem cell treatments be developed for corneal diseases? This horizon scanning review was undertaken in response to this question, to determine what, if any, technological and procedural breakthroughs are imminent for the treatment of corneal disorders.

1.1. CLINICAL NEED AND BURDEN OF DISEASE Corneal disorders such as corneal dystrophies, advanced keratoconus, keratitis and corneal neovascularisation can cause severe sight loss1. In 2009-2010, 1,911 people of working age (between 16 and 64 years) diagnosed with severe sight impairment were certified as blind in England and Wales2. Corneal disorder was cited as the main or contributory cause in 4.1% of these cases2. In England between March 2014 and March 2015, there were 4,807 primary diagnoses of corneal disorder and 16,831 inpatient procedures for corneal disorders (including main procedures [11,160] and interventions [5,671], OPCS4 codes C44-C51). Most of the main procedures related to corneal grafting and transplant3,4. Corneal disorder or injury can result in: • abrasion, erosion, and surface irregularities (usually the result of band keratopathy, corneal scarring, nodular degeneration, epithelial basement membrane dystrophy or other dystrophies) • astigmatism reducing visual acuity (caused by an irregularly-shaped cornea, e.g keratoconus, ]

or scarring) • infection (e.g. infectious keratitis and keratoconjunctivitis) • inflammation • limbal stem cell deficiency, which can be congenital or as a result of damage to the limbal area,

preventing the repair of corneal damage • oedema • opacity (as a result of injury, autoimmune diseases, bullous keratopathy, keratoconus, keratitis

and corneal stromal dystrophies e.g. Fuch’s endothelial dystrophy) • perforation • thinning • transplant rejection • ulceration

The UK Transplant Registry recorded 3,789 donor corneal transplants in 2015-20165 for the treatment of severe corneal disorder. Of those with a reported disorder (3,451), around one-third were performed for sight loss due to endothelial dysfunction, e.g. Fuch’s endothelial dystrophy, and around a fifth each were performed for regrafts (e.g. due to rejection), astigmatism i.e. keratoconus and other ectasias, and corneal oedema post cataract surgery (Figure 1)5. In the UK, there has been a 75% overall increase in corneal transplants since the year 2000. This rise is directly attributable to an increase in transplants for endothelial disorders like Fuchs dystrophy, regrafts (for rejection, primary and endothelial corneal failure, high astigmatism, and endophthalmitis) and other previous ocular surgeries (for aphakic and pseudophakic corneal oedema, and complications of refractive surgery) (Figure 2). An Italian study which has reported the same findings has accredited this rise to an aging population, an increase in the number of cataract surgeries, and the recent emergence of endothelial keratoplasty procedures6. Donor corneas for transplant are limited and transplants require life-long immunosuppression therefore other treatment options are needed, particularly for endothelial disorders, failed or rejected grafts, and failed surgeries.

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Figure 1: UK Standard National Cornea Transplant Dataset: Primary diagnosis of recipients of donor corneas 2015-2016 (Data provided by NHS Blood and Transplant – UK Transplant Registry)

Figure 2: UK Standard National Cornea Transplant Dataset: Number of recipients of donor corneas by diagnosis in 2000, 2005, 2010 and 2015 (Data provided by NHS Blood and Transplant – UK Transplant Registry)

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1.2. CURRENT TREATMENT In many cases adjunctive treatment of corneal disorders is required for symptom relief (e.g. photophobia, anterior chamber reaction [irritation] and pain). Severe photophobia is managed with cycloplegic agents (to prevent pupil spasm). Pain is managed with non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. General irritation to the cornea caused by improper tearing, e.g. in the case of exposure and neurotrophic keratopathies, is managed with lubricants and in severe cases tarsorrhaphy (temporary suturing together of the eye lids). Current treatment options for primary disorders of the cornea are listed below7- 14:

1.2.1. ABRASION, EROSION OR SURFACE IRREGULARITES

Corneal abrasion or erosion15

First line • removal of the foreign body • topical corticosteroids

Adjunctive • Topical antibodies

Recurrent erosions syndrome of the cornea and scarring16

First line • removal of scar tissue, lubrication, bandage contact lens • topical medication • autologous serum

Recurrent or requiring surgical intervention

• anterior stromal puncture • mechanical debridement e.g. resurfacing keratectomy

(using a diamond burr) • phototherapeutic laser keratectomy (removal of the

cornea epithelium using alcohol followed by the further removal of minute layer using an excimer laser)

• lamellar keratoplasty (LK, host endothelium and Descemet’s membrane is retained)

Refractory • corneal transplant Surface irregularities17 • phototherapeutic laser keratectomy

1.2.2. ASTIGMATISM

Irregular astigmatism, keratoconus-or keratectasia-related18- 20

1st line or mild to moderate

• spectacle or rigid gas-permeable (RGP) contact lens correction with riboflavin eye drops

2nd line • piggy-back, hybrid, or scleral lenses

3rd line or progressive

• intrastromal corneal ring segment (ICRS) inserts • topography-guided excimer laser surgery; • photo-astigmatic refractive keratectomy (PRK) corneal

cross-linking alone or in combination with ICRS, PRK or phakic intraocular lens (PIOL) implantation

4th line or severe

• penetrating (whole thickness corneal transplant) or deep lamellar keratoplasty (host Descemet’s membrane and endothelium retained)

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1.2.3. INFECTIOUS KERATITIS

Bacterial keratitis

1st line

• topical combination antibiotics, topical quinolone, topical polymyxin B-trimethoprim combination or sulfacetamide (with or without cycloplegics)

Adjunctive • topical steroids (to aid healing) Viral keratitis

1st line

• topical antiviral therapy (with or without cycloplegics) or oral antiviral therapy plus topical corticosteroids

Fungal keratitis 1st line • cornea scraped and topical 2nd line

• oral antifungal therapy or therapeutic penetrating keratoplasty

Protozoal keratitis

1st line

• topical amoebicides in combination with topical steroids, antiseptics

Adjunctive • oral itraconazole or voriconazole (topical or systemic) Severe • therapeutic penetrating keratoplasty

Rosacea keratitis

1st line

• topical ciclosporin • oral antibiotics • topical steroids

1.2.4. INFLAMMATION

Non-infectious keratitis

1st line

• topical or systemic steroids (prednisolone ophthalmic [1%] or loteprednol ophthalmic [0.5%])

Keratoconjunctivitis

1st line

• lubricants • antihistamines • topical corticosteroids

2nd line or steroid sparring

• topical 0.05% or 2% ciclosporin suspended in oil or systemic ciclosporin

Refractory • topical or systemic tacrolimus Keratoconjunctivitis, vernal subtype (in children)

• mast cell stabilisers e.g. gutt sodium cromoglicate 2%,

gutt lodoxamide 0.1%)

1.2.5. LIMBAL STEM CELL DEFICIENCY

Limbal stem cell deficiency as a result of trauma, burns, inflammatory or hereditary disease 21

Mild • lubricants, topical steroids and bandage contact lenses • autologous serum

Severe

• tissue-cultured limbal stem cell allograft transplant (from relative or cadaver) • amniotic membrane grafts with or without uncultured limbal stem cell grafts • conjunctival and keratolimbal allografts or corneal graft

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1.2.6. OEDEMA

Corneal oedema Acute • topical hypertonic sodium chloride and topical atropine

1.2.7. OPACITY

Severe opacity

1st line

• penetrating keratoplasty (PK) with allogeneic cornea • lamellar keratoplasty • endothelial keratoplasty - Descemet’s membrane and endothelium transplanted (DSEK [Descemet’s Stripping Endothelial Keratoplasty] or DSAEK [Descemet’s Stripping Automated Endothelial Keratoplasty] and EK)22

2nd line or contraindicated for 1st line

• keratoprosthesis (artificial cornea) • corneal graft-keratoprosthesis (hybrid human artificial

cornea)23 • Insertion of hydrogel keratoprosthesis24

Opacity caused by endothelial dysfunction

1st line

• corneal endothelial transplantation (with a cadaveric donor endothelial graft)

1.2.8. PERFORATION

Superficial perforation

1st line • Tissue adhesive

Severe perforation 1st line • Lamellar keratoplasty

• Penetrating keratoplasty

1.2.9. THINNING

Dellen of the cornea (example)

• lubricants

1.2.10. TRANSPLANT REJECTION

Corneal transplant rejection

1st line • topical steroid, intensive adjuvant • systemic steroid/immunosuppressant therapy

Endothelial rejection severe • systemic steroids Any transplant rejection

With history of herpes simplex infection

• topical antiviral

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1.2.11. ULCERATION

Mooren’s ulcer • topical steroids, topical antibiotics or systemic steroids Dendritic corneal ulcers • antivirals (acyclovir or ganciclovir)

2 AIMS

The aim of this horizon scanning review was to produce a report for Fight for Sight and the JLA Sight Loss and Vision PSP on new and emerging technologies and procedures in development for the treatment of corneal disorders. 3 METHODS

A protocol was developed stating the intended aims and objectives, identification sources, inclusion and exclusion criteria, methods, and timeframe for this review. This was agreed with a representative from Fight for Sight. An expert advisory group was established to provide input throughout the horizon scanning review process (Appendix 1). Fight for Sight also convened two patient focus groups to contribute to the review.

3.1. IDENTIFICATION

3.1.1. ELECTRONIC IDENTIFICATION SOURCES

We searched a wide range of on-line sources of intelligence including:

1. Bibliographical databases 2. Clinical trial registries 3. Commercial pharmaceutical and medical technology databases. 4. HSRIC’s confidential ‘in-house’ database of technologies 5. Internet search engine – Google 6. MedTech industry news sites 7. Opthalmology groups and networks 8. Other medical horizon scanning databases 9. Professional conference proceedings 10. Regulatory authorities 11. Research funding databases

A complete list of the identification sources searched is presented in Appendix 2. The search terms used are presented in Appendix 3.

3.1.2. OTHER IDENTIFICATION SOURCES

We contacted Medilink West Midlands, a national health technology business support organisation, who sent out a call via Twitter to their UK stakeholders to ask whether they were developing any

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relevant technologies. We also asked the expert advisory group and patient focus groups if they knew of any new developments for corneal disorders.

3.2. INVESTIGATION AND FILTRATION Further information was sought on the technologies identified either through an internet search or by contacting developers. The technologies identified were then filtered using the criteria listed in Table 1. Filtration was initially carried out by the analyst, then by another member of the internal review team. Some technologies were excluded following input from the expert advisors after the assessment of impact stage. Table 1: Review inclusion and exclusion criteria

Key filtration points

Inclusion criteria Exclusion criteria

Technology type • Advanced Therapy Medicinal Products (ATMPs) - classified as somatic cell therapies, gene therapies, and tissue engineering products)

• Devices • Pharmaceuticals • Procedures

• Diagnostic tests • Prognostic tests • Prophylactic treatments

Place in pathway Treatment Screening, diagnosis, prognostic and prevention

Clinical area Acquired and congenital disorders of the cornea (ICD-10: neoplasms - C69, D31; endocrine, nutritional and metabolic diseases – E50.2, E50.3, E50.6; disorders of sclera, cornea, iris and ciliary – H16, H17.0, H17.1, H17.8, H17.9, H18, H19.1, H19.2, H19.3, H19.8; congenital malformation, deformations and chromosomal abnormalities – Q13.3, Q13.4; injury, poisoning and certain other consequences of external causes – S05.3, T15.0, T26.1, T26.6; factors influencing health status and contact with health services – Z52.5), adults and children.

Stage in development

• Emerging: novel technologies or procedures being evaluated within a research setting only – in phase II or III clinical trials.

• Emerging: novel medical devices to be CE marked or launched in the UK within the next 2 years, CE marked or launched within the past year, or CE marked or launched within the

• Preclinical research. • Very early or late stage

developments, phase 0 and IV clinical research.

• Technologies already established for clinical use in the NHS.

• New ‘incremental’ changes to established procedures.

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past 2 years and poorly diffused. Study type • Clinical trials

• Case studies • Studies before 2014 • Studies that are terminated,

withdrawn or status unknown Research locations

All locations

Developer type Commercial Academic institutes

3.3. ASSESSMENT OF IMPACT To assess the potential impact of the new and emerging technologies identified, the filtered list with accompanying information was presented for comment to two patient focus groups and an expert advisory group (Appendix 1).

3.3.1. PATIENT FOCUS GROUPS

Fight for Sight arranged two focus groups with people who have first-hand experience of corneal disorders. The participants had the following disorders:

• 2 with Fuchs endothelial corneal dystrophy • 3 with keratoconus • 1 with complex/multiple causes of visual impairment including congenital glaucoma with

recurrent ‘sloughing’ of corneal epithelium • 1 with complex/multiple causes of visual impairment including aniridia

Participants were asked the following questionsa by a facilitator from the JLA:

• Which one or two treatments in the list stand out for you? o What was your overarching impression? o What makes them stand out? o How do you feel about them?

• Which, if any, of the treatments do you think are particularly innovative or interesting? • Did you already know anything about any of the treatments?

o What are your perceptions of availability and usage?

• Are there any treatments in the list which do not appeal to you? Why?

3.3.2. EXPERT ADVISORY GROUP

Members of the expert advisory group (Appendix 4) were asked to comment on the following:

Innovation: • Is this technology or procedure innovative?

a With permission from Kathrine Cowan, James Lind Alliance.

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• What features do you believe are innovative? • Significance of the innovation?

Impact: • Is this technology or procedure likely to have a significant impact on patient outcomes or

NHS systems and resources? • Are there any other potential impacts of this technology or procedure? • Likely timeframe for impact? Adoption: • Does this technology or procedure seem likely to be adopted into UK practice? • What are the foreseeable barriers to its adoption?

Evidence: • How good is the evidence base so far? And what kind of further research is needed?

We also asked the clinical experts some questions posed by the patient focus groups:

• What impact would the technology or procedure have on the need for after care? • How would the new technology or procedure when compared with current treatment

impact on recovery? • Would the new technology or procedure bring an improvement in long term benefits?

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4 RESULTS

One hundred and thirty new and emerging technologies for the treatment of corneal disorders were included in the final list following filtration (Figure 3). A summary of these innovations is presented by treatment type for each indication group in Figure 4, by indication in Table 2, and by technology type in Table 3, with full details for each technology or procedure presented in Appendix 5. Figure 3: Horizon scanning review identification and filtration flow diagram

Filtered out: Expert filter (n=24)

Filtered out: final HSRIC filter (n=184)

Included technologies (n=130)

Technologies considered by expert group (n=154)

Filtered out: initial HSRIC filter (n=47)

Not relevant (n=3,150)

Technologies after initial HSRIC filter (n=338)

Search hits (n=3,535)

Technologies identified (n=385)

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Figure 4: Number of technologies by technology type for each indication group.

4.1. TECHNOLOGIES BY INDICATION Table 2 provides the number of new and emerging technologies and procedures identified for each indication. Most innovations were in development for keratoconus. Table 2: Identified technologies and procedures — by indication

Indication group Indication Number identified

Abrasion, erosion or surface irregularities (n=11)

Corneal epithelial disorder 3 Ocular Surface Disease 1 Persistent Corneal Epithelial Defects 6

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Recurrent corneal erosion syndrome 1

Astigmatism (n=34)

Corneal astigmatism 1 Corneal ectasia (Keratectasias) 4 Corneal graft astigmatism 1 Irregular corneas 1 Keratoconus 24 Keratoconus and corneal ectasia 2 Keratoglobus 1

Burns (n=4) Chemical and thermal burns 1 Chemical burns 2 Ocular surface burns 1

Cystinosis (n=1) Cystinosis 1

Disorder not otherwise specified (NOS) (n=16)

Corneal damage 1 Corneal disease 8 Corneal transplantation 7

Endothelial disease (n=11)

Bullous keratopathy 5 Bullous keratopathy or Fuchs' dystrophy 2 Corneal endothelial disease 3 Fuchs' Corneal Endothelial Dystrophy 1

Epithelial inclusion cyst (n=1) Recurrent intrastromal epithelial inclusion cyst in a corneal graft 1

Graft rejection (n=1) Corneal endothelial failure 1

Infection (n=13) Corneal endotheliitis 1 Keratitis 9 Keratoconjunctivitis 3

Inflammation (n=3) Corneal post-operative inflammation 1 Keratoconjunctivitis 2

Keratoconjunctival disease, non-infectious (n=1) Keratoconjunctival disease 1

Neoplasia (n=2) Corneal limbal dermoids 1 Ocular surface squamous neoplasia 1

Nerve disorder (n=4) Corneal sensation loss 1 Keratitis, neurotrophic 3

Oedema (n=4) Corneal oedema 1 Corneal oedema, postoperative 3

Opacity (n=3) Corneal blindness 2 Corneal opacity 1

Pain (n=1) Ocular Pain 1

Perforation (n=2) Corneal Perforations 1 Pterygium, recurrent 1

Pterygium (n=1) Pterygium, primary 1

Stem cell deficiency (n=12) Corneal epithelial stem cell deficiency 2 Corneal opacity 1

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Limbal stem cell deficiency 6 Ocular Surface Disease 2 Ocular surface stem cells deficiency 1

Thinning (n=2) Corneal stromal thinning 1 Corneal thinning 1

Ulcer (n=3) Corneal ulcer 3 Total 130

4.1.1. ABRASION, EROSION OR SURFACE IRREGULARITIES

In total, there were 10 technologies and one procedure in development for the treatment of abrasions, erosions or surface irregularities. Nine of these technologies were for corneal epithelial defects (#2, #3, #15, #55, #70, #75, #77, #81, #82), one for corneal erosion syndrome (#80) and one for ocular surface disease (#14). The technologies included: an allogeneic human umbilical cord blood serum (#3); autologous whole blood (#2); two non-limbal stem cell therapies (autologous [#15] and allogeneic [#14]); six drugs; and one procedure. The drugs included an anti-inflammatory agent (#55), a peroxisome proliferator activated receptor δ (PPARδ) agonist to aid rapid wound healing (#70), a neurotrophic peptide (#77), a formulation of corneal matrix proteins (#75), and two formulations of synthetic tears (#80 and #81). The identified procedure was the use of the anterior capsule of a donor lens as a ‘collagen shield’ to decrease friction from the eye lid and aid healing (#82).

4.1.2. ASTIGMATISM

There were 9 technologies and 25 procedures in development for the treatment of astigmatism. The vast majority, 30 in total, were for keratoconus and other corneal ectasia (#17, #38, #42, #45, #46, #72, #83, #90-#104, #110-#117), one for corneal astigmatism (#47), one for corneal graft astigmatism (#48), one for irregular corneas (#37) and one for keratoglobus (#125). These included: one tissue layer (Bowman layer transplanted midway in the keratoconic cornea) (#17); one drug, a formulation of matrix proteins (#72); seven devices; and 25 procedures. The devices included two scleral contact lenses, one with an artificial tear reservoir (#37 and #38); a device using microwaves to flatten the protruding cone of keratoconus (#42); four implants to correct astigmatism - three intraocular lenses (#45-#47) and one intrastromal corneal ring (#48). The procedures included 16 variations on the existing collagen crosslinking (CXL) procedure, a method of strengthening and stabilising the cornea to prevent any further protrusion, and included trials in children, with epithelium left on, accelerated CXL, or CXL in combination with technologies that correct astigmatism (#83, #90-#104); five keratectomies in combination with CXL to simultaneously correct the refractive error and stabilise the cornea (#110-#114); two conductive keratoplasties, i.e. radiofrequency energy applied to the periphery of the cornea to induce shrinkage, to increase the curvature of the cornea and so increase refractive power - with and without CXL (#115 and #116); a laser-masking agent to prevent corneal perforation (#117); and a modified anterior lamellar keratoplasty to correct vision by correcting the structural abnormalities associated with keratoglobus (#125).

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4.1.3. BURNS

There were three technologies and one procedure in development for the treatment of corneal burns. Two of the developments were specifically for the treatment of chemical burns (#4 and #119) and the remaining two for any type of burn (#39 and #58). The technologies included: one biological therapy, an allogeneic umbilical cord serum eye drop (#4) with the potential to be available off-the-shelf; one device, a scleral contact lens with a reservoir filled with saline (#39); one drug, an antisense therapy to downregulate the inflammatory response (#58); and one procedure, the use of a limbal autograft from the fellow eye in combination with hyperbaric oxygen to aid healing (#119).

4.1.4. CORNEA DISORDER (NOT OTHERWISE SPECIFIED)

In total, 13 technologies and 3 procedures were identified for treating corneal disorders that were not otherwise specified, nine for corneal disease or damage (#1, #7, #32, #34, #41, #50, #51, #106, and #127) and the remaining seven for corneal transplantation (#22, #29, #33, #43, #44, #49 and #105). The treatments comprised: three cell and biological therapies including allogeneic plasma drops (#1), autologous limbal epithelial stem cells in fibrin gel (#7) and a gamma irradiated acellular cornea to act as a scaffold for autologous cells (#22); three procedures including two donor cornea preparations, one cushion to enable cutting of donor corneas with narrow scleral rims which would normally disqualify them for use (#105) and one involving preconditioning to enable the production of microthin grafts (#106), and a partial thickness corneal transplant in combination with a prosthesis (#127); and ten devices. The ten devices included four artificial corneas made from materials including fish scales (#29), hydrogels (including a foldable cornea (#32) and one that can be cut to complement the host tissue bed (#33)), and titanium (#51); a biometry device which integrates tomography, topography and biometry (#34); a corneal graft delivery device which allows a smaller incision, so reducing endothelial cell loss (#41); two viscoelastic gels to protect the corneal endothelium during surgery (#43 and #44); a hydrogel liquid ocular bandage to protect from eyelid trauma (#49); and a microscopic ocular surgical tool to remove scar tissue (#50).

4.1.5. CYSTINOSIS

One drug was identified that was in development for the treatment of cystinosis, a cystine antagonist (#64).

4.1.6. ENDOTHELIAL DISEASE

Three technologies and eight procedures were identified for the treatment of corneal endothelial disease, five developments were specifically for bullous keratopathy (#84, #122, #123, #128 and #130), one specifically for Fuch’s corneal endothelial dystrophy (#108), two for the treatment of both bullous keratopathy and Fuch’s corneal endothelial dystrophy (#5 and #6), one for endothelial keratoplasty (#107), and the remaining two for corneal endothelial disease not otherwise specified (#40 and #126). The identified technologies included: two cell therapies composed of corneal endothelial cells with manipulation of the Rho-ROCK cytoskeletal signalling pathway (to modulate cell adhesion and

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engraftment), one in combination with a Rho inhibitor (#5), and the other with a ROCK inhibitor (#6); one device for ultrathin endothelial graft insertion (#40); and eight procedures. The procedures included CXL to alleviate discomfort and pain (#84); donor cornea deturgescence to enable ultrathin endothelium preparation (#107); central Descemet membrane keratectomy (#108); a stain to highlight tissue during DMEK surgery (#130); and four variations on endothelial keratoplasty (#122, #123, #126 and #128) (see Appendix 4 for figure: Layers of the cornea).

4.1.7. EPITHELIAL INCLUSION CYST

A procedure was identified for the treatment of epithelial inclusion cyst, lamellar excision and donor lamellar placement (#124).

4.1.8. GRAFT REJECTION

A drug was identified for the treatment of acute endothelial corneal graft rejection, an immunosuppressant to inhibit the activation of T-cells intended for use as an adjunctive to conventional steroid therapy (#68).

4.1.9. INFECTION

Nine technologies (all drugs) and four procedures were identified for the treatment of corneal infection, one development for cytomegalovirus corneal endothelitis (#63), nine for microbial keratitis (including acanthamoebal, bacterial, fungal or viral keratitis) (#53, #57, #60, #66, #69, #86-#89) and three for infectious keratoconjuntivitis caused by bacteria, adenovirus or the ectoparasite demodex (#61, #62 and #71). The identified procedures were all variations on CXL using the photo-activation of riboflavin as a pathogen inactivation therapy (#86-#89). The nine drugs included an antifungal agent (#53); two antiseptic therapies (#60 and #61); two antiviral agents (#62 and #63); a pesticide (#71); an immunomodulator to reduce swelling in the eye (#66); a nicotinic receptor antagonist and interferon gamma stimulator, derived from snake venom, to counteract viral infection (#69); and an antisense therapy to prevent pathogenic neovascularisation (#57).

4.1.10. INFLAMMATION

Three technologies were identified for the treatment of inflammation, two for keratoconjunctivitis (#65 and #67) and one for corneal post-operative inflammation (#54). The technologies identified were all drugs: two immunomodulators, one to decrease swelling to enable tear production (#65), and the other inhibiting the activation of T-cells (#67); and an anti-inflammatory which also suppresses oxidative stress (#54).

4.1.11. KERATOCONJUCTIVAL DISEASE, INTRACTABLE

A cell therapy was in development for the treatment of intractable keratoconjunctival disease, a cultivated autologous oral mucosal epithelial cell sheet for transplant (#27).

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4.1.12. NEOPLASIA

There were two advances for the treatment of neoplasia, one for ocular surface squamous neoplasia (#56) and one for corneal limbal dermoids (#129). The treatments identified were drugs, topical chemotherapy with 5-fluorouracil or mitomycin-C (#56); and a procedure, encompassing simple excision, corneal tattooing, and sutureless limboconjunctival autograft (#129).

4.1.13. NERVE DISORDER

Four technologies were identified for the treatment of corneal nerve disorders, three for neurotrophic keratitis (#73, #78 and #79) and one for corneal anesthesia (#25). The technologies included one tissue transplant which was transplantation of a segment of the medial cutaneous branch of the sural nerve from the calf of the leg (#25); and three drugs, a formulation of corneal matrix proteins (#73), a synthetic version of an endogenous matrix metalloproteinase modulator for wound healing (#78), and a recombinant human nerve growth factor (#79).

4.1.14. OEDEMA

Four developments were identified for the treatment of corneal oedema, two for corneal oedema following cataract surgery (#35 and #120), one for postoperative oedema (#118) and one for corneal oedema of any cause (#36). Those identified included two devices, both hyperosmotic contact lenses that extract fluid by osmosis (#35 and #36); and two procedures, magneto-photophoresis (treatment with a photosensitizing agent and light under the influence of a magnetic field) (#118) and transcorneal oxygen therapy to reduce endothelial cell hypoxia, as an adjunct to conventional therapy (#120).

4.1.15. OPACITY

Three advances were identified for the treatment of corneal opacity, one for corneal opacities due to anterior corneal dystrophies (#109) and the other two for corneal blindness (#30 and #31). Two of the developments were devices, both artificial corneas, one a biosynthetic corneal scaffold as a matrix for ingrowth of the recipients own cells (#30), and the other foldable and injectable into a partial thickness corneal pocket using a small incision (#31); the third was a procedure, femtosecond laser-assisted lamellar keratectomy to remove part of the central corneal free cap (#109).

4.1.16. PAIN

A drug was identified that was in development for the treatment of corneal pain, a gene silencing RNA interference (RNAi) therapy which targets the capsaicin receptor, a mediator of inflammation and pain (#59).

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4.1.17. PERFORATION

Two developments were identified for the treatment of corneal perforation, one for small corneal perforations (#21) and one for recurrent pterygium (#16). Both were tissue transplants, variations on amniotic membrane transplants, one a fibrin glue-assisted amniotic membrane transplant-plug (#21), and the other dried amniotic tissue with adhesive (#16).

4.1.18. PTERYGIUM

A tissue transplant procedure was in development for the treatment of primary pterygium invading more than 1mm onto the cornea. It was a superficial conjunctival autograft of the primary pterygium after excision at the site of primary pterygium with no suture and no fibrin glue (#18).

4.1.19. STEM CELL DEFICIENCY

In total, 12 technologies were identified for the treatment of stem cell deficiency: two for corneal epithelial stem cell deficiency (#19 and #24); one for corneal opacity (#13); six for limbal stem cell deficiency (#8, #9, #11, #20, #23 and #28); one for ocular surface disease arising from epithelial stem cell deficiency (#26); one for ocular surface disease arising from limbal stem cell deficiency (#10); and one for any ocular surface stem cell deficiency (#12). Four of the technologies were ocular cell transplants, a limbal epithelial transplant using double-layered cryopreserved amniotic membrane (source, autologous or allogeneic, not reported) (#8), allogeneic limbal stem cells cultured on human amniotic membrane with immunosuppressive therapy (#9), autologous limbal stem cells ex-vivo expanded on human amniotic membrane with immunosuppressive therapy (#10), and autologous ocular surface epithelial stem cells administered via contact lens delivery (#11). Two involved the use of autologous oral mucosa epithelial stem cells, one in combination with autologous ocular surface epithelial stem cells (#12) and the other on human amniotic membrane (#13). The remaining six were tissue transplants: a corneal epithelial cell sheet cultivated on human bone marrow mesenchymal stem cell-derived feeder cells, (source, autologous or allogeneic, not reported) (#19); autologous cultivated corneal epithelium (#20); an annular keratolimbal allograft with simultaneous en-bloc central penetrating keratoplasty and peripheral lamellar keratoplasty (#23); an autologous limbal epithelial cell sheet cultivated on human amniotic membrane, human serum- and feeder cell-free (#24); an autologous cultivated oral mucosal epithelial cell sheet transplantation, (#26); and an autologous ex-vivo expanded oral mucosal epithelium, feeder- and animal product-free (#28).

4.1.20. THINNING

Two developments were identified for corneal thinning, one for progressive thinning (#74) and one for stromal thinning (#121). One of these was a drug, a formulation of corneal matrix proteins (#74), and the other was a procedure, a corneal stromal transplant (#121).

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4.1.21. ULCER

Three advances were identified for corneal ulcer, one for refractory ulcer (#76), one for infectious or bacterial ulcers recalcitrant to conventional topical and subconjunctival antibiotics (#85), and one for any type of corneal ulcer (#52). Two of these were drugs, honey as an antibacterial agent (#52), and a synthetic version of an endogenous enzyme cofactor, which is thought to prevent cell death (apoptosis), and is intended to be used as an adjuvant therapy (#76). Tthe other advance was a procedure, corneal CXL (#85).

4.2. TECHNOLOGIES BY TYPE Table 3 provides the number of new and emerging technologies and procedures identified by technology type. The greatest number of developments were procedures using innovative ways of corneal cross linking (CXL). Table 3: Identified technologies and procedures — by type

Technology type Number identified

Biological and cellular therapies (n=28) Human serum 4 Ocular cells, stem or other 7 Non-ocular adult cells 2 Non-ocular stem cells 2 Tissue transplant 13

Devices (n=23) Artificial cornea 6 Biometry 1 Contact lens, osmotic (absorbent) or scleral/corneoscleral 5 Corneal graft delivery device 2 Device delivering microwaves to the cornea 1 Gel to cushion and protect corneal tissue during surgery 2 Intraocular lens 3 Intrastromal corneal ring/inlay 1 Ocular bandage 1 Surgical device for creating incisions in the cornea 1

Drugs (n=30) Antibacterial 1 Antifungal 1 Anti-inflammatory 2 Antimetabolite 1 Antisense or RNA interference 3 Antiseptic 2 Antiviral 2 Cystine antagonist 1 Immunomodulation 4 Nicotinic receptor antagonists 1 Peroxisome proliferator activated receptor δ (pparδ) agonists 1

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Pesticides 1 Synthetic or recombinant biologics (Proteins, peptides, or polysaccharide) 8 Synthetic tears 2

Procedures (n=49) Biological bandage 1 Corneal cross linking 22 Donor cornea preparation 3 Keratectomy or Keratectomy in combination with CXL 7 Keratoplasty 2 Laser- masking agent 1 Magneto-photophoresis 1 Oxygen to aid recovery 2 Partial thickness corneal transplant 8 Simple excision and conjunctiva covering 1 Stain to highlight tissue during surgery 1

Total 130

4.2.1. BIOLOGICAL AND CELLULAR THERAPIES

The majority of cellular and biological therapies identified by this review were for the treatment of corneal stem cell deficiency, half of these were cell therapies (#8-#13), while the other half were tissue transplants (#19, #20, #23, #24, #26, #28). Therapies included ocular stem cells delivered using a contact lens (#11), oral mucosal epithelial stem cells or tissue transplants (#12, #13, #26, #28), cells grown into a membrane on feeder cells (#19), grown on amniotic membranes (#8, #9, #10), autologous limbal transplants (#20, #24) and a keratolimbal allograft (#23). Cellular therapies for the treatment of endothelial diseases (#5, #6), ocular surface disease (#7, #14) and persistent corneal epithelial defects (#15) were also identified. The expert group commented that emerging endothelial cell therapies “will have a significant impact on the management of corneal endothelial failure globally” and have a “huge impact on the current practice of endothelial keratoplasty, promising to deliver minimally invasive corneal/cell transplantation”. For the treatment of epithelial disorders an expert commented that the “oral mucosal epithelium/epithelial cell sheet could be useful where autologous corneal epithelial stem cells are absent”. The transplant of the patient’s own cells/tissue spurred the most interest in the patient focus groups. Autologous cell therapies were perceived by the focus groups to be safer, with no transplant rejection, and with a view that the treatment outcome would last longer. This was on the proviso that cells harvested would have to be ‘healthy’. Conversely, the impact of stimulating a patient’s in situ cells, e.g. RGN-259 for endogenous stem cell recruitment to treat neurotrophic keratitis (#78), was questioned by the focus groups. The use of allogeneic tissue was raised as a concern in the patient focus groups because of the need for life-long immunosuppression. A gamma irradiated cornea, fundamentally a corneal scaffold extricated of donor cells and so non-immunogenic, was identified (#22). An autologous nerve transplant for corneal sensation loss (#25) and variations on amniotic tissue transplants for corneal perforation (#16, #21) were also identified. The emerging allogeneic plasma drops (#1) and umbilical cord serums (#3, #4), which contain cytokines, chemokines, growth factors and other biological factors to aid healing, may have the potential to be an off-the-shelf alternative to the currently used autologous serum, and were deemed by the experts to be “very promising for the treatment of ocular burns”, “had the potential to be used in inflammatory ocular surface disease”, and “could be the only source of plasma drops in children or cases of plasminogen deficiency when patient’s own bloods cannot be used”, although

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there would be “a need for further safety and efficacy studies”. Autologous finger prick whole blood was also in clinical trials as an alternative (#2). A number of the advances in biological and cellular therapies identified were in development ‘outside’ of Europe, therefore although the clinical experts noted the potential of these emerging technologies, the trials “may not be recognised by the European Regulators as relevant enough to the European population and standards.”

4.2.2. DEVICES

Many of the novel devices identified were for the treatment of astigmatism and included phakic and pseudophakic intraocular lenses (#46-#48), scleral lenses (#38-#40), an intrastromal inlay (#49) and a device using microwaves to flatten the protruding cornea (#43). Absorbent osmotic contact lenses were emerging for the treatment of oedema (#36, #37), artificial corneas for opacity (#29-#34), and scleral contact lens for burns (#38-#40) - providing protection from eyelid friction without resting on the limbal area which is vital to repair. Osmotic contact lenses would, one expert commented, be “useful in cases where endothelial transplantation is not possible or in waiting for such procedures”. The expert group commented that “there is a need for scleral contact lenses in difficult cases” of irregular corneas and corneal burns, and they were a “unique principle, promising in dry eye, corneal surface disease”. One patient who was a recipient of a corneal transplant was particularly interested in the use of artificial corneas as a method of making the surface of his eye smoother, as the unevenness of the surface of the transplanted tissue had left him with problems with receiving light. Devices for graft insertion were identified that would access smaller incisions to minimise endothelial cell loss during transplant procedures (#41, #42).

4.2.3. DRUGS

Most of the emerging drugs were for the treatment of infectious keratitis, but in addition to antifungal (#53), antiseptic (#60, #61), and antiviral (#62, #63, #69) treatments there was also a novel use of an antisense therapy (#57) to regulate the expression of inflammatory cytokines and angiogenic growth factors to prevent pathogenic neovascularisation. Immunomodulators were also in development for keratitis, and also keratoconjunctivitis (#65-#68). An emerging focus on accelerating natural wound healing is also apparent with the development of synthetic or recombinant biological molecules. These included matrix proteins (#72-#75), human nerve growth factors (#79), neurotrophic factors (#77), and metalloproteinases modulators (#78), some of which were also in development to halt the progression of corneal thinning (#72) and keratoconus (#74). A synthetic enzyme cofactor was also identified for the prevention of cell death in corneal ulcer (#76). Synthetic tears were in development for the treatment of persistent corneal epithelial defects (PCEDs) and corneal erosion syndrome (#80, #81). The expert group commented that the “area of novel biologics for the cornea is important and will develop considerably over the following decade” and that the technologies identified were “promising”. Honey for the treatment of corneal ulcers (#52), one of the most unusual technologies identified, exhibiting anti-microbial, anti-biofilm and anti-inflammatory properties, was heralded by the expert group as innovative, however the participants on the focus groups were not enthusiastic about this approach. Other anti-inflammatory agents were identified for the treatment of post-operative inflammation and PCED (#54, #55), and anti-sense and RNA interference anti-inflammatory agents for ocular burns (#58) and ocular pain associated with dry eye syndrome (#59).

4.2.4. PROCEDURES

Almost half of the advances in procedures were intended to alleviate or prevent the progression of keratoconus and other ectasia (#83, #90-#104). The majority of these were enhancements to the

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standard cross-linking procedure, many of which could be deemed as incremental innovations. However, the novel use of cross-linking in the treatment of resistant and persistent infectious keratitis (#85-#89) was seen to be “promising” by the expert group. Innovations in keratectomy in combination with cross-linking to treat keratoconus were also numerous (#110-#114). The removal of the central descemet membrane to treat Fuch’s dystrophy (#108), was seen as innovative and “an alternative to endothelial keratoplasty” by the expert group. Several procedures were intended for the pre-conditioning of corneas to produce ultra-thin grafts with the intention to reduce surgical “invasiveness” when compared with penetrating keratoplasty (#105-#107). Non-invasive conductive keratoplasties for the treatment of keratoconus and other ectasia (#115, #116) were also discovered. The novel use of oxygen to aid the recovery of corneal burns and corneal oedema after surgery was identified (#119, #120), but although “interesting” was seen to have limited use by the experts as it required a hyperbaric chamber.

4.3. GENERAL COMMENTS ON NEW AND EMERGING TECHNOLOGIES

4.3.1. PATIENT COMMENTS

For many of the participants in the patient focus group, treating the debilitating symptoms encountered with corneal disorders in their day-to-day lives was as much of a priority as a ‘cure’. For instance participants felt instinctively that treatments which reduced inflammation were “logical and sensible”. It was commented that tacrolimus (#67), which was identified for allergic reactions, would have a huge positive affect on quality of life (especially during hay fever season) because it would be used to relieve allergies which severely impede tolerance to contact lenses. Participants with endothelial disorders particularly commented on the need to address symptoms e.g. the need to reduce overnight fluid accumulation which temporarily distorted vision and prevented the undertaking of everyday tasks until the fluid assuaged with time. One patient with this condition dried their eyes with a hairdryer. Another theme that arose was the ‘practicality of use’ of treatments and their delivery e.g. eye drops which require refrigeration, and the application of ‘corneal bandage lenses’ by patients themselves without causing damage to the surface of the cornea. Generally, the patient focus groups preferred treatments with lower immediate and long term risk, for instance, incisions to the eye required to implant an intraocular lens was perceived to add risk, and invasive treatment was seen as a last resort. The participants also commented on the poor reputation of corrective laser eye surgery which meant the perception of all laser treatments was negative. The stage of sight loss journey of the participants impacted on their perception of risk with participants who had recently been diagnosed more cautious about invasive treatment options than those with disorders from birth. Fight for Sight identified a number of aspects to be considered when developing or implementing new technologies, these can be found in Appendix 6.

4.3.2. EXPERT COMMENTS

Overall, the experts determined that there is a need for more treatments for endothelial disease including “improvements in corneal endothelial treatment (ultra-thin DSAEK [Descemet's stripping automated endothelial keratoplasty], better DMEK [Descemet's membrane endothelial keratoplasty}

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methods, transplantation of cultured corneal endothelial cells and agents to improve corneal endothelial cell survival)” and “novel agents/drops for the treatment of poor corneal epithelial and/or endothelial healing;”. For cellular therapies, they felt that the use of pluripotent/mesenchymal stem cells for corneal regeneration needs to be studied further. Although this review identified a large number of emerging treatments for keratoconus, an expert determined that additional methods for visual rehabilitation in keratoconus are also needed. One expert also highlighted the development and increasing use of a number of existing biologic agents in the management of severe ocular surface inflammation. These include immunoglobulins, rituximab and infliximab, but were excluded from this review as development is at an early stage and/or these agents are currently being used off-label. 5 DISCUSSION

This review identified multiple biological and cellular therapies, devices, drugs and procedures for the treatment of corneal disorders. Of the biological and cellular therapies, cellular therapies were identified as promising by both the expert group and patient focus groups, although patients preferred autologous treatments whilst the experts saw the potential of allogenic treatments. Limbal stem cell deficiency can lead to loss of corneal transparency, resulting in severe visual impairment. The autologous limbal stem cell therapy, Holoclar, has recently been licensed in Europe for the treatment of ocular burns. Although limbal autografts from the healthy eye, like Holoclar, have the advantage of not requiring immunosuppression, there is a risk of this procedure causing a ‘limbal stem cell deficient state’ in that eye25, and autologous ocular stem cell therapies are not an option in bilateral ocular stem cell deficiency. Even though the expert group clearly identified a need for an allogeneic option, stating that it “could make limbal stem cell transplantation easier to achieve” they also noted that “the adoption of allogeneic therapy in Europe was not yet realised”. This review identified a limbal allograft (allogeneic limbal stem cells grown on amniotic membrane in combination with immunosuppressant) (#9) that could potentially be used off-the-shelf, and a number of technologies that employ novel ways to improve the adherence of transplanted cells. From the cell therapy regulatory perspective, it was remarked that the “vast majority of the therapies listed are [being] developed by academic organisations; the lack of a commercial partner suggests that either the benefits are not established yet and/or that these therapies may try to reach the market through the hospital exemptions route (as the fully licensed route would be too expensive for such establishments)”. Also, given that “the target indication for many of [these new technologies] being limbal stem cell deficiency for which we now have a licensed equivalent in the UK (Holoclar), major adoption potential for such therapies may not be anticipated”. In devices, the patient focus groups were most interested in artificial corneas, and the experts noted the potential of osmotic contact lenses for the treatment of oedema. For the identified drugs, patients were most interested in technologies that treated symptoms like tacrolimus for allergic reactions, and the expert group saw biologics as an area for potential growth. In procedures, keratectomy to remove individual diseased tissue layers for the treatment of endothelial disease was determined to be innovative and promising by the expert group. In many instances the procedures identified for the treatment of endothelial disease were mainly nuances on partial thickness corneal transplants, using them in combination with other treatments like cross-linking with or without intrastromal implants. It has been reported that the recently adopted lamellar keratoplasties have a worse graft survival than penetrating grafts6. However, this review identified advances in this area that could help overcome some of the technical difficulties encountered in these procedures, such as the use of the microkeratome in ultrafine Descemet

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stripping pocketmaker endothelial keratoplasty. Conversely, the focus groups preferred the non-invasive procedures identified, such as conductive keratoplasty. Cross-linking to treat corneal infection was another procedure thought to be interesting by the expert group. The number of corneal transplants in the UK has been steadily increasing in the last two decades5 (Figure 3) and this review has identified the emergence of much needed alternatives. These include artificial corneas, gamma irradiated acellular corneas - potentially non-immunogenic with a 2 year shelf-life - and a process to allow the use of donor corneas that are currently rejected because they have a narrow scleral rim. The expert group commented that “alternative sources for corneal tissue needed in transplantation are important”, that the devices identified were “promising” and “innovative and creative methods to generate new artificial cornea[s]” and “an answer to hundreds of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection”. This review identified a large number of emerging technologies for the treatment of keratoconus and many for keratitis and oedema which, if successful, could lead to a drop in the number of corneal transplants for these indications in the future. Only one development for regrafts was identified, an endothelial transplant to remedy failed penetrating keratoplasty. Novel technologies to combat endothelial disorders such as Fuch’s disorder were also lacking. Participants of the patient focus groups were very interested in a number of the emerging technologies identified. Their main concerns with new technologies included practicality of use; risks associated with treatment; benefits and effectiveness when compared with current treatment options; how outcomes will be measured; and pre- and post-treatment care. Of the 130 technologies identified only 33 were being developed by a commercial developer, the remaining 97 were being developed by an academic institution or hospital, of which only 31 were in development in Europe, with the vast majority of the remainder being developed in Asia. Also, 12 of the developments, comprising biological and cellular therapies (including mesenchymal stem cells and a gamma irradiated cornea), devices (including artificial corneas) and procedures were reported as case studies. This would mean that many of the technologies, although determined by the expert group to be innovative and in some cases a much needed treatment option, are currently very early in development, with little if any evidence yet to support their adoption. Such technologies are unlikely to become part of NHS care in the short to medium term, and may fail to materialise if early results are not promising. 6 CONCLUSION

The aim of this review was to identify new and emerging technologies for the treatment of disorders of the cornea. We identified a number of novel cellular and other biological therapies in development answering the Sight Loss and Vision PSP question ‘Can new therapies such as gene or stem cell treatments be developed for corneal diseases?’ We also identified a number of innovative devices, drugs and procedures. Although there are many technologies and procedures in development for the treatment of keratoconus and other ectasia, emerging treatments for endothelial diseases and graft failure, the leading causes of sight loss in corneal disease and main consumers of corneal transplants, appear to be lacking. Also a large number of the developments identified during this review were in non-European clinical trials.

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7 APPENDICES

APPENDIX 1. EXPERT ADVISORY GROUP

Mr Romesh I Angunawela: • Consultant Eye Surgeon: Cornea, Cataract and Refractive Surgery, Moorfields Eye Hospital,

London. • Honorary Senior Lecturer, UCL and St George's University of London.

Specialty: Keratoconus surgery: collagen cross linking, keraring implantation and lamellar corneal transplant surgery and contact lens fitting, Dry eye disease, Blepharitis and meibomian gland dysfunction and Sjogren’s disease. Interests: Complex corneal disease, laser eye surgery, cataract surgery, corneal transplantation Conflict of interest: none stated

Dr Sajjad Ahmad: • Senior Clinical Lecturer in Ocular Stem Cell Biology, Department of Eye and Vision Science,

Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool.

• Honorary Consultant Ophthalmologist, Cornea and External Eye Diseases, St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool.

Specialty: Corneal and ocular surface stem cell biology Interest: Translational research into corneal and ocular surface disease Conflict of interest: expert advisory board for Chiesi and Santen; undertaking multi centre European trial for corneal epithelial stem cells.

Mr Samer Hamada: • Consultant Ophthalmic Surgeon: Cornea, Cataract, External Eye Disease, and Refractive

Surgery in Children and Adults, Queen Victory Hospital, East Grinstead; The Wellington Hospital, London; and Great Ormond Street Hospital for Children NHS Trust, London.

Specialty: Congenital paediatric corneal disease, cornea and anterior segment surgery Interest: New innovations for managing patients with corneal diseases Conflict of interest: none stated

Mr Panos Kefalas: • Head of Health Economics and Market Access, Cell and Gene therapy Catapult, London.

Conflict of interest: None

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APPENDIX 2: ELECTRONIC SOURCES OF INTELLIGENCE USED TO IDENTIFY TECHNOLOGIES

Source Website Not publically

available

General internet Google https://www.google.co.uk/ ZETOC database - British Library Database http://zetoc.jisc.ac.uk/ Horizon scanning websites & databases Agency for Healthcare Research and Quality (AHRQ)

http://www.effectivehealthcare.ahrq.gov

CADTH https://www.cadth.ca ECRI Institute http://www.ecri.org √ EuroScan International Network www.euroscan.org Restricted

access for non-members

HSRIC ‘in-house’ technology database Not online √ NIHR BRCs, BRU, CRF, HTC and DEC dataset (2013-14)

Confidential internal document from NIHR NETSCC

√

Commercial pharmaceutical and medical technology databases Adis http://bi.adisinsight.com/ √ GlobalData Medical http://www.globaldata.com/ √ Pharmaprojects https://nhsc-

pipeline.citeline.com/CpAccount.aspx √

Clinical trial registries ClinicalTrials.gov http://clinicaltrials.gov/ WHO International Clinical Trials registry platform (ICRTP)

http://apps.who.int/trialsearch/AdvSearch.aspx

Research funding databases i4i portfolio of funded projects http://www.nihr.ac.uk/research/inventi

on-for-innovation_1.htm

NIHR Evaluation Trials and Studies Project portfolio

http://www.nets.nihr.ac.uk/projects?collection=netscc&meta_P_sand=Project

UKCRN portfolio database http://public.ukcrn.org.uk/search/ MedTech industry news sites Clinica MedTech http://www.clinica.co.uk/ √ Fierce Network – Fierce Diagnostics: Medical Imaging

http://www.fiercediagnostics.com/topics/medical-imaging

GlobalData Medical http://www.globaldata.com/ √ Medical News Today http://www.medicalnewstoday.com/ MedGadget http://www.medgadget.com/ Licensing bodies European Medicines Agency (EMA) http://www.ema.europa.eu/ema/index.

jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

US Food and Drug Administration http://www.fda.gov/medicaldevices/productsandmedicalprocedures/

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Bibliographic databases Ovid MedLine(R) In-process & Embase (to current date)

http://www.elibrary.bham.ac.uk/

Conference proceedings Annual Meeting of the Association for Research in Vision and Ophthalmology

http://www.arvo.org/

ASCRS ASOA Symposium and congress https://ascrs.confex.com/ Cornea Day http://corneaday.org/ European contact lens society of opthalmologists

http://www.eclso.eu/

European Society for Cataract and Refractive Surgery Meeting

http://www.escrs.org/

European Society of Cornea & Ocular Surface Disease Specialists – Eucornea Congress

http://www.eucornea.org/

Royal College of Ophthalmologists Annual Meeting

https://www.rcophth.ac.uk/

Relevant groups and networks Corneal Transplant Foundation www.corneal-transplant-

foundation.org/

Moorfields Eye Hospital

http://www.moorfields.nhs.uk/

National Eye Institute (NIH, USA) https://nei.nih.gov/

The Royal College of Ophthalmologists https://www.rcophth.ac.uk/ Journals The Ocular Surface http://www.theocularsurfacejournal.com

/

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APPENDIX 3. SEARCH TERMS USED

Disease search terms Intervention search terms Innovation search terms

Adherent leukoma *keratopathy* advanced therapy medicinal product advances

Arcus senilis Keratoconus cell therapy alternative

*cornea* Keratoglobus device emerging

Crocodile shagreen Krukenberg spindle drugs in development

Descemetocele Late congenital syphilitic oculopathy gene therapy innovative

Dystrophia Smolandiensis Mooren ulcer pharmaceuticals new

Dystrophia Helsinglandica Pellucid marginal degeneration procedure novel

*endothelial dystrophy Peter anomaly regenerative therapy

*epithelial dystrophy Reis-Bücklers dystrophy therapy

Fold in Descemet membrane Rupture in Descemet membrane treatment

*dyskeratosis* Salzmann Nodular Degeneration

Kayser-Fleischer ring spheroidal degeneration

Keratitis Hudson-Staehli line

Keratoconjunctivitis Vogt's* limbal girdle

* indicates use of truncation

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APPENDIX 4. LAYERS OF THE CORNEA

Structures of the Eye. Source:: National Eye Institute, National Institutes of Health (NEI/NIH). Used with permission

35

APPENDIX 5A. NUMBER OF DEVELOPMENTS BY TYPE AND INDICATION GROUP

Number of Biological and Cell Therapies per indication:

Indication group

Technology type Abrasion, erosion or surface irregularity

Astigmatism Burns Disorder NOS

Endothelial disease

Kerato-conjunctival disease, other

Nerve disorder

Perforation Pterygium Stem cell deficiency

Total

Human serum 2 1 1 4 Ocular cells, stem or other

1 2 4 7

Non-ocular adult cells

2 2

Non-ocular stem cells

2 2

Tissue transplant 1 1 1 1 2 1 6 13

Total 4 1 1 3 2 1 1 2 1 12 28

Number of Devices per indication:

Indication group

Technology type Astigmatism Burns Disorder NOS Endothelial disease

Oedema Opacity Total

Artificial cornea 4 2 6 Biometry 1 1 Contact lens, osmotic (absorbent)

2 2

Contact lens, scleral/corneoscleral 2 1 3 Corneal graft delivery device 1 1 2 Device delivering microwaves to 1 1

36

the cornea Gel to cushion and protect corneal tissue during surgery

2 2

Intraocular lens 3 3 Intrastromal corneal ring/inlay 1 1 Ocular bandage 1 1 Surgical device for creating incisions in the cornea

1 1

Total 7 1 10 1 2 2 23

Number of Drugs (by mechanism of action) per indication:

Indication group

Technology mechanism of action

Abrasion, erosion or surface irregularity

Astigmatism Burns Infection Inflammation Neoplasia Nerve disorder

Thinning Ulcer Cystinosis Pain Graft rejection

Total

Antibacterial 1 1

Antifungal 1 1 Anti-inflammatory

1 1 2

Antimetabolite 1 1 Antisense or RNA interference

1 1 1 3

Antiseptic 2 2

Antiviral 2 2 Cystine antagonist

1 1

Immuno- modulation

1 2 1 4

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Nicotinic receptor antagonists

1 1

PPARδ agonists 1 1

Pesticides 1 1

Synthetic or recombinant biologics

2 1 3 1 1 8

Synthetic tears 2 2

Total 6 1 1 9 3 1 3 1 2 1 1 1 30

* PPAR δ, Peroxisome proliferator activated receptor Number of Procedures per indication:

Indication group Technology type Abrasion,

erosion or surface irregularity

Astigmatism Burns Disorder NOS

Endothelial disease

Epithelial inclusion cyst

Infection Neoplasia Oedema Opacity Thinning Ulcer Total

Biological bandage 1 1

CXL 16 1 4 1 22 Donor cornea preparation

2 1 3

Keratectomy 1 1 2 Keratectomy in combination with CXL

5 5

Keratoplasty 2 2 Laser- masking agent 1 1 Magneto-photophoresis

1 1

38

Oxygen to aid recovery

1 1 2

Partial thickness corneal transplant

1 3 1 1 6

Partial thickness corneal transplant in combination with prosthesis

1 1

Partial thickness corneal transplant using microkeratome pocket maker

1 1

Simple excision and conjunctiva covering

1 1

Stain to highlight tissue during surgery

1 1

Total 1 25 1 3 8 1 4 1 2 1 1 1 49

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APPENDIX 5B. DEVELOPMENTS (DESCRIPTION & FURTHER INFORMATION)

*Stage of development includes: trial ID; phase; country; number of patients; and trial status

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Biological and cellular therapies

Patient focus groups:

• There was widespread interest in treatments which involved stem cells taken from the patient with a belief that this will mean less likelihood of rejection. The sight people have is precious so anything which ‘feels’ safer is preferable.

• Transplant patients do not want to have to take drugs forever therefore anything which minimises the risk of rejection is welcomed. There was an assumption that anything made from patient’s own stem cells would last longer (sic. Be effective for a longer term).

• This was however balanced with caution that the health professional would have to be sure the cells harvested were healthy.

Human serum

Expert: Autologous and allogeneic serums are available in the UK but access to them is overly restricted due to cost. Expert: Growth factor and other humeral factors promote healing

1 Allogenic plasma drops

Corneal disorder Developer: Copenhagen University Hospital, Denmark. Description: Serum derived from allogeneic whole-blood.

Systematic review of studies between 2008 & 2011, compassionate use only; Denmark; n=34

Expert: Could be the only source of plasma drops like in children or cases of plasminogen deficiency when patient’s own bloods cannot be used http://onlinelibrary.wiley.com/doi/10.1111/aos.12386/full

2 Autologous whole blood from fingerprick

Persistent Corneal Epithelial Defects (PEDs);

Developer: Bedford Hospital NHS Trust. Description: growth factors in the

NCT02153515; Phase 3; UK; n=4; n=60

Expert: This is in trial phase and results are encouraging. Expert: Not practical, but can be a temporary source of autologous serum drops until getting access to more

40

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

(FAB) Chronic corneal epithelial defects; Chronic Corneal Ulcers

serum may improve the ocular surface. A drop of blood was produced using a standard diabetic lancet and applied to the lower fornix of the affected eye.

traditional technology like access to serum drops Expert: Useful as this is a readily available source of serum if this is shown to work. May not be palatable to patients however. http://www.escrs.org/london2014/programme/posters-details.asp?id=20543

3 Umbilical cord serum eye drops

Corneal epithelial defect, post cornea transplantation, post keratoplasty

Developer: All India Institute of Medical Sciences - Center for Ophthalmic Sciences, New Delhi (India) Description: Eyedrops prepared from umbilical cord serum to aid re-epithelialisation of the corneal graft after transplantation.

CTRI/2014/01/004361; IRCT138903241180N15; Phase 2; Phase 2/3; India; Iran; n=105; n=80; Completed

Expert: This is a developing novel therapy and not available in the UK at present Expert: Good principle but need more evidence to prove efficacy and safety http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2014/01/004361

4 Umbilical cord serum eye drops

Ocular chemical burns, acute

Developer: Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (India) Description: Umbilical cord serum with amniotic membrane transplantation in cases of acute ocular chemical burns.

India; n=55 eyes Expert: This is a developing novel therapy and not available in the UK at present Expert: Very promising therapy in cases of ocular chemical burns, and open the door for other applications such as acute inflammatory ocular surface disease http://dx.doi.org/10.1136/bjophthalmol-2014-305760

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# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Ocular cells, stem or other

Expert: Epithelial stem cells/transplants could make limbal stem cell transplantation easier to achieve. Easily applicable in clinical practice.

5 Corneal endothelial cell, cultivated, combined with Rho inhibitor mesenchymal-conditioned medium, and an inhibitor of transforming growth-factor beta signalling.

Corneal endothelial damage: bullous keratopathy or Fuchs' dystrophy

Developer: Kyoto Prefectural University (Japan) Description: cells combined with a Rho kinase inhibitor, mesenchymal-conditioned medium, and an inhibitor of transforming growth-factor beta signalling. Inhibition of Rho signalling may modulate actin cytoskeletal dynamics through Rho-ROCK signalling activity, potentially serving as a cell-based regenerative medicine with enhanced cell adhesion and so engraftment.

UKCRN 4872; Phase N/K; UK; n=11

Expert: This will have a significant impact on the management of corneal endothelial failure globally. Expert: Success in this mode of therapy will have huge impact on current practice of endothelial keratoplasty, promising to deliver minimally invasive corneal/cell transplantation Expert: could potentially be very useful in the treatment of conditions such as Fuchs’ endothelial dystrophy without the need for surgery https://www.ukctg.nihr.ac.uk/

6 Corneal endothelial cell, cultured, injected in combination with Y-27632 (ROCK inhibitor)

Keratopathy, bullous (caused by corneal endothelial diseases such as Fuchs Endothelial Corneal Dystrophy)

Developer: Senju Pharmaceuticals; Kyoto Prefectural University of Medicine (Japan) Description: Injection of cultured human corneal endothelial cell into the anterior chamber. Inhibition of ROCK signalling may manipulate cell adhesion through Rho-ROCK signalling activity (please see above).

JPRN-UMIN000012534; N/K; Japan; n=22; Open public recruiting

Expert: This will have a significant impact on the management of corneal endothelial failure globally. Expert: Success in this mode of therapy will have huge impact on current practice of endothelial keratoplasty, promising to deliver minimally invasive corneal/cell transplantation Expert: could potentially be very useful in the treatment of conditions such as Fuchs’ endothelial dystrophy without the need for surgery. Promising results in animal

42

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

modelshttp://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000012534

7 Limbal epithelial stem cells, autologous, in fibrin gel

Ocular surface burns, Corneal epithelial cell deficiency, dysfunctional corneal endothelial cells; Corneal disease, corneal scars

Developer: Tej Kohli Cornea Institute, L. V. Prasad Eye Institute (India); University of California Los Angeles - Department of Human Genetics & Broad Stem Cell Research Center (USA) Description: Stem cells were collected from tiny biopsies in the limbus of the undamaged eye, cultured and incorporated into a gel of fibrin, a protein commonly used as a surgical adhesive. The gel was spread on the damaged cornea.

India, n=126; USA, n=10

Expert: There is currently a European multi-centre trial and national autologous and allogeneic trials have been done. Expert: To my knowledge this work was developed in India not the USA. http://www.ncbi.nlm.nih.gov/pubmed/26896125

8 Limbal epithelial transplantation (modified simple) using cryopreserved amniotic membrane

Limbal Stem Cell Deficiencies, primary, secondary, syndrome or unilateral

Developer: Agentschap voor Innovatie door Wetenschap en Technologie (Belgium); Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (France) Description: Simple limbal epithelial transplantation using a double-layered cryopreserved amniotic membrane graft. The use of a double layer allows more protection for the explant

EUCTR2013-004247-24-BE; Phase 2; Belgium; n=60

Expert: There is currently a European multi-centre trial and national autologous and allogeneic trials have been done. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013-004247-24-BE

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# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

without impacting outcomes. Also, the use of cryopreserved amniotic membrane allows surgeons to perform this procedure in the USA.

9 Limbal stem cells, allogeneic, cultured on human amniotic membrane with immunosuppressive therapy

Limbal stem cell deficiency

Developer: Scottish National Blood Transfusion Service, NHS Lothian, and NHS Greater Glasgow and Clyde (UK) Description: Ex vivo expansion of limbal stem cells, from cadaveric donor tissue, on human amniotic membrane transplantation with immunosuppression.

UK; n=10 Expert: The adoption of allogeneic therapy across Europe is to be realised yet. Expert: This has been in clinical practice for good time and won’t consider it as new innovation https://www.scotblood.co.uk/media/101706/research_development_innovation_strategy_2012_17.pdf

10 Limbal stem cells, autologous, ex vivo expanded on human amniotic membrane with immunosuppressive therapy

Ocular surface disease arising from limbal stem cell deficiency, unilateral

Developer: Shanxi Medical University - Department of Clinical Medicine (China); Newcastle University (UK); NHS Lothian Princess Alexandra Eye Pavilion, UK Stem Cell Foundation (UK) Description: A small limbal biopsy is taken from the healthy eye of each patient and the limbal stem cell population expanded ex vivo on to human amniotic membrane (HAM) (unlike Holoclar), and then transplanted into the prepared disease eye (i.e. via superficial

ISRCTN54055321, Phase N/K, UK, n=20, completed; EudraCT 2011-000608-16 (ISRCTN51772481, UK CRN 11185), Phase 2, UK; n=24; completed

Expert: There is currently a European multi-centre trial and national autologous and allogeneic trials have been done. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN54055321

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# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

keratectomy) combined with a second HAM (stroma facing down) on top as a biological bandage.

11 Ocular surface epithelial stem cells, autologous, via contact lens delivery

Limbal stem cell deficiency, total and partial

Developer: University of New South Wales (Australia) Description: Autologous limbal or conjunctival epithelial biopsies harvested from patients were placed on the concave surface of silicone hydrogel contact lenses. Cells were expanded in culture with autologous serum and transplanted onto the ocular surface.

ACTRN012607000211460; Phase N/K; Australia; n=16 (16 eyes)

Expert: The use of a contact lens carrier is novel. Expert: No good evidence to support efficacy and safety. http://dx.doi.org/10.1186/s13287-015-0009-1

Non-ocular cells (in combination with or without ocular cells)

12 Ocular surface epithelial stem cells, autologous, and oral mucosa epithelial stem cells, autologous

Ocular surface stem cells deficiency

Developer: Eye Institute of Xiamen University (China) Description: Ex-vivo expansion and transplantation of autologous oral mucosal epithelial stem cell with autologous corneal epithelial stem cell and autologous conjunctival epithelial stem cell for ocular surface reconstruction.

ChiCTR-OCB-15005973; Phase N/K; China; n=30; recruiting

Expert: The long-term results of this from Japan are already published. Expert: New promising technology to restore ocular surface in cases of stem cell deficiency. No immunosuppression treatment is not necessary, favourable by patients. We are doing our own study at QVH and results so far are promising. Expert: Unsure how this mixed phenotype of cells would work in practice. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=Chi

45

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

CTR-OCB-15005973

13 Oral mucosal epithelial cells, autologous, on human amniotic membrane, allogeneic

corneal opacities, bilateral, due to bilateral limbal stem cell deficiencies

Developer: Dr. R. P. Centre, AIIMS - Dept. of Ophthalmology (India) Description: Ocular surface reconstruction with autologous oral mucosal epithelial cells on a human amniotic membrane graft.

CTRI/2009/091/000906; N/A; India; n=20; Open to recruitment

Expert: The long-term results of this from Japan are already published. Expert: No extra advantage of growing cells on amniotic membrane http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2009/091/000906

Non-ocular stem cells

14 Embryonic stem cell derived epithelial cells, human, allogeneic

Ocular Surface Disease, Severe

Developer: Eye Institute of Xiamen University (China) Description: Human embryonic stem cell derived epithelial cells transplantation.

ChiCTR-OCB-15005968; Phase N/K; China; n=20; Recruiting

Expert: The use of pluripotent stem cells for corneal regeneration needs further study. Expert: Promising resource of corneal stem cells Expert: May be a ready source of epithelial cells if these cells remain viable http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-OCB-15005968

15 Mesenchymal stem cells, adipose-derived, autologous

persistent corneal epithelial defect

Developer: University Hospital of Heraklion, Crete - Eye Clinic (Greece) Description: Lipoaspirate was obtained by limited liposuction of subcutaneous adipose tissue of the lumbar area. Adipose-derived mesenchymal cells (ADMC) were isolated. Three million cells in a final volume of 50μl were transferred into the bottom of the

Greece; case study

Expert: The use of mesenchymal stem cells for corneal regeneration needs further study. Expert: Weak evidence based on single case report. Expert: Still experimental. http://www.sciencedirect.com/science/article/pii/S1319453414000770

46

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

ulcer. Following application and adherence onto the corneal tissue, a pressure eye patching was applied for 24 hours.

Tissue transplant Expert: Oral mucosal epithelium/epithelial cell sheet could be useful where autologous corneal epithelial stem cells are absent.

16 Amniotic membrane, dried with tissue adhesive

Corneal perforations, recurrent pterygium

Developer: Toyama University Hospital Ophthalmology (Japan) Description: Novel dried amniotic membrane, part of the placenta, is harvested after birth and used with tissue adhesive in ophthalmic surgery.

JPRN-UMIN000002983; Phase N/K; Japan; n=250

Expert: We have access to several forms of amniotic membrane in the UK Expert: Efficacy is less than fresh Amnion http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000002983

17 Bowman layer transplantation

Keratoconus, progressive advanced, not eligible for ultraviolet cross-linking

Developer: Parker Cornea (USA); Netherlands Institute for Innovative Ocular Surgery (Netherlands) Description: During a Bowman layer transplant, a donor Bowman layer is surgically transplanted into a pocket created midway in the keratoconic cornea. By supplementing that layer with strong, healthy tissue, the cornea is flattened and progression of keratoconus can be arrested and even partly reversed. This technique avoids the need for more invasive sutured

NCT01686906, Phase N/K, Netherlands, n=100, recruiting; USA, n=19 (22 eyes), completed

Expert: This is a small study and the benefit of this over DALK is unclear. Expert: This technology is less in use, due to lack of strong evidence on efficacy and safety Expert: Innovative new surgical technique. Further independent evidence of efficacy is required. This trial will be useful http://parkercornea.com/new-treatment-for-advanced-keratoconus-to-be-performed-at-parker-cornea/

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# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

corneal transplant procedures, such as PK and DALK.

18 Conjunctival autograft, superficial, of the primary pterygium after excision at the site of primary pterygium with no suture and no fibrin glue

Primary pterygium, invading more than one mm onto the cornea

Developer: Karnataka Institute of Medical Sciences, Vidyanagar, HUBLI - Dept of ophthalmology (India) Description: Free conjunctival autograft surgical procedure over the bare sclera following pterygium excision without sutures or fibrin glue.

CTRI/2012/01/002366, phase N/K, n=100, completed; CTRI/2014/12/005251, phase N/K, India, n=25, completed

Expert: Published data shows that a conjunctival autograft is superior. Expert: Nothing new or innovative http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2012/01/002366

19 Corneal epithelial cell sheet, cultivated, on human bone marrow mesenchymal stem cell-derived feeder cells, (source i.e. autologous or allogeneic

corneal epithelial stem cell deficiency; chemical/ thermal burns of the cornea; Salzmann Corneal Degeneration

Developer: Keio University School of Medicine - Department of Ophthalmology (Japan) Description: Surgical procedure involving removal of all pannus and abnormal epithelial tissue, the use of 0.04% mitomycin C to prevent fibrosis, and transplantation of cultivated corneal epithelial sheet transplantation (using human corneal epithelial stem cells and human bone marrow mesenchymal stem cell-

JPRN-UMIN000002948; Phase N/K; Japan; n=5; Open public recruiting

Expert: The use of a different culture system for growing corneal epithelial stem cells is novel but there are good treatments already available. Expert: would benefit a narrow spectrum of patients http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000002948

48

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

unknown) derived feeder cells).

20 Corneal epithelium (EYE-01M), cultivated, autologous

Limbal stem cell deficiency

Developer: Japan Tissue Engineering Co.,Ltd. (Japan) Description: Removal of limbal tissue and cultivated autologous corneal epithelial transplantation.

JPRN-UMIN000018969; Phase N/K; Japan; n=10; open public recruiting

Expert: As above, already trialled. Expert: Innovative modality of limbal stem cell transplantation http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000018969

21 Fibrin Glue-Assisted Amniotic Membrane Transplant-Plug (FG-assisted AMT-plug)

Corneal Perforations, small

Developer: Canakkale Onsekiz Mart University, School of Medicine - Department of Ophthalmology (Turkey) Description: An AMT was folded in on itself twice by using FG then a small piece of this FG-AMT mixture was cut to maintain an appropriate plug for the site of the corneal perforation. The FG-assisted AMT-plug was placed in the perforation area by using FG. An amniotic membrane patch was placed over the plug, which was then secured by a bandage contact lens.

Turkey; case study

Expert: Small study. http://www.hindawi.com/journals/criopm/2014/351534/

22 Gamma irradiated cornea

cornea transplantation

Developer: Slovak Medical University (Slovakia) Description: Gamma irradiated

Slovakia; case study

Expert: Novel method for utilising donor corneal tissue. Expert: Current methods to store corneas for later use as tectonic tissue is using cornea immersed in100%

49

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

corneas considered as an alternative to fresh donor corneas for lamellar grafts. An irradiated cornea has no cells and so is not immunogenic. The resulting corneal stroma has normal collagen structure, is transparent and has same thickness as the fresh cornea. It can be stored at room temperature for two years and also is no risk of transmission diseases from donor to recipient.

ethanol. Expert: evidence of efficacy and complications such as rapid absorption need to be assessed. This could be a source of corneal tissue where there are shortages. http://www.seeos.eu/index.php/2015/12/17/anterior-lamellar-keratoplasty-using-gamma-irradiated-corneal-graft-an-innovative-approach-regarding-alk-2/

23 Keratolimbal allograft, Annular (KLAL) transplantation via simultaneous en-bloc central penetrating keratoplasty (PK) and peripheral lamellar keratoplasty (LK)

limbal stem cell deficiency, severe

Developer: Labbafinejad Medical Center, Tehran - cornea and anterior segment surgery service (Iran) Description: Central PK and peripheral LK with annular KLAL transplantation by one surgeon at the same surgical setting using tissue from a unique donor who received a combined immune suppressive protocol including mycophenolate mofetyl, tacrolimus and prednisolone.

Iran; n=7 (7 eyes)

Expert: This is an alternative to cultivated corneal epithelial stem cells for severe injuries.

Expert: Difficult to assess efficacy. Likely to be of limited use as requires prolonged immunosuppression.

http://staging.ophthalmologytimes.advanstar.com/ophthalmologytimes/news/en-bloc-pk-klal-novel-approach-severe-limbal-stem-cell-deficiency

50

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

24 Limbal epithelial cell sheet, cultivated, autologous, on human amniotic membrane, human serum- and feeder cell-free

Corneal epithelial stem cell deficiency/total limbal stem cell deficiency, Unilateral : Patients who have dysfunction of the entire limbus with almost replaced by conjunctival epithelium, neovascularization and corneal scarring tissue.

Developer: The University of Tokyo, Graduate School of Medicine - Department of Ophthalmology (Japan) Description: Serum- and feeder cell-free cultivated autologous corneal limbal epithelial cell sheet transplantation using human amniotic membrane. Corneal limbal epithelial tissue is extracted from a patient's own healthy eye, and a limbal epithelial cell sheet using human amniotic membrane is produced.

JPRN-UMIN000012014; Phase N/K; Japan; n=3; No longer recruiting

Expert: As above, many trials published on this. Expert: Will reduce transmission of xenomaterials and possible transmissible diseases. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000012014

25 Nerve transfers and nerve grafts, regional

corneal sensation loss

Developer: University of Toronto, Hospital for Sick Children - Department of Ophthalmology and Vision Sciences (Canada) Description: Novel sensory reconstructive technique for the treatment of corneal anaesthesia. Corneal sensory reconstruction was performed using a segment of the medial cutaneous branch of the sural

Canada; n=3 (4 eyes)

Expert: Novel but there are nerve growth factor drops being developed. Expert: Very innovative method to restore corneal sensation (corneal neurotisation), will open the door to management of thousands of cases with neurotrophic corneas. At QVH we have been doing this since early 2016 with very encouraging initial outcomes Expert: potential treatment for neuropathic corneas has shown promise

51

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

nerve. http://dx.doi.org/10.1001/jamaophthalmol.2014.2316

26 Oral mucosal epithelial cell sheet transplantation, autologous, cultivated

ocular surface disease, severe intractable, with corneal epithelial stem cell deficiency

Developer: Tohoku University Graduate School of Medicine - Department of Ophthalmology (Japan) Description: Cultivated autologous oral mucosal epithelial cell sheet transplantation for corneal epithelial stem cell deficiency.

JPRN-UMIN000006745, n=10; JPRN-UMIN000005400, n=10; JPRN-UMIN000012264, n=10; JPRN-UMIN000012260, n=10, Phase N/K, Japan

Expert: Long term results already available for this. Expert: No immunosuppression treatment needed, suitable for bilateral cases http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000006745

27 Oral mucosal epithelial cell sheet transplantation, autologous, cultivated

Keratoconjunctival disease, intractable (Stevens-Johnson syndrome, ocular pemphigoid, or severe thermal/chemical injury)

Developer: Kyoto Prefectural University of Medicine (Japan) Description: Cultivated autologous oral mucosal epithelial sheet transplantation.

JPRN-UMIN000012819; Phase 1, 2; Japan; n=30; Open public recruiting

Expert: Long term results already available for this. Expert: No immunosuppression treatment needed, suitable for bilateral cases http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000012819

28 Oral mucosal epithelium, cultivated, ex vivo expanded,

Corneal limbal stem cell deficiency, bilateral

Developer: Royal Victoria Infirmary, Newcastle University - Institute of Genetic Medicine and Departmentof Ophthalmology (UK)

Proof of concept; UK; n=2

Expert: Long term results already available for this from Japan. Expert: Initial work in Japan Kinoshita’s group has shown efficacy and safety. This publication provided

52

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

autologous, feeder- and animal product-free

Description: Ocular surface reconstruction with ex vivo expanded limbal stem cells (LSCs) is not available to people with bilateral LSC deficiency. Cultivated oral mucosa epithelium (OME) has been used as an alternative source of autologous epithelial stem cells generated as a multilayered OME epithelium that shares many of the characteristics of corneal epithelium using a fully compliant good manufacturing practice, feeder- and animal product-free method.

further evidence from two cases with 24 months follow ups (very small sample) http://dx.doi.org/10.1002/stem.1694

Devices

Artificial cornea

Patient focus groups: A participant who had been the recipient of much treatment throughout his life welcomed the thought of an artificial cornea which could make the surface of his eye smoother making it easier.

29 Artificial cornea, Biocornea

Corneal transplantation surgery for disorders including limbal stem cell deficiency, chemical burn,

Developer: Aeon Astron (Netherlands) Description: Biocornea is a fully degradable artificial cornea designed to dissolve completely and regenerate corneal tissue. It is derived from fish tilapia scales and is semi transparent with 3-D in structure; constructed with nanofibrils with porous networks.

Clinical development; Phase U/K; Germany

Expert: Alternative sources for corneal tissue needed in transplantation are important. Expert: Innovative and creative methods to generate new artificial cornea. An answer to hundreds of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection. Expert: Interesting. Actual efficacy is yet to be proven.

53

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

and corneal repair

It is a collagen scaffold with biocompatibility, biodegradability and cell initiation and growth properties. It is based on soft hydrous gel which allows glucose and other nutrients to pass through in promoting the growth of cells.

Patient focus groups: The treatment which includes the fish scales was seen as not suitable for vegetarians or may have potential cultural implications. http://www.aeonastron.com/rd.php

30 Artificial cornea, Eyegenix

Corneal blindness Developer: Eyegenix (USA); University of Ottawa (Canada) Description: Eyegenix Artificial Cornea is a bioengineered, synthetic, transplantable corneal implant designed to replace the damaged or diseased cornea. It is made up of a bio-integrating polymer corneal substitute. It is designed as a tissue scaffold that uses biosynthetic collagen to encourage cells from the recipient to grow into the graft and mimic natural healing.

Clinical development; Phase I completed (EudraCT 2006-006585-42, Sweden, n=20, 10 with Eyegenix); class III device; estimated approval July 2017, estimated launch October 2017

Expert: Alternative sources for corneal tissue needed in transplantation are important. Expert: Innovative and creative methods to generate new artificial cornea. An answer to hundred of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection. Expert: Actual efficacy is yet to be proven. Promising http://www.eyegenix.com/wp-content/uploads/2016/02/biomaterials-article.pdf

31 Artificial cornea, KeraKlear

Cornea blindness Developer: KeraMed Inc. (USA) Description: KeraKlear is a foldable and injectable artificial cornea designed to be implanted into a partial thickness corneal pocket using small incision (3.5 mm in diameter) by using femtosecond laser or robotic device to restore vision. It may be

Approved in Europe

Expert: Alternative sources for corneal tissue needed in transplantation are important. Expert: Innovative and creative methods to generate new artificial cornea. An answer to hundreds of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection. Expert: insufficient detail to assess how this would

54

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

implanted in most patients with corneal blindness without penetration into the anterior chamber.

work. Needs proof of concept http://www.healio.com/ophthalmology/cornea-external-disease/news/print/ocular-surgery-news/%7B2c1dd25c-be15-45b4-9ba5-cf5ff27e9695%7D/keraklear-keratoprosthesis-an-option-for-treating-corneal-blindness

32 Artificial cornea, KeraKlear XT (variable thickness non-penetrating foldable)

Corneal scars, corneal dystrophies, corneal oedema, limbal stem cell deficiency and keratoconus

Developer: KeraMed Inc (USA) Description: KeraKlear XT is a variable thickness non-penetrating foldable artificial cornea which has been developed to be implanted at the appropriate depth. It can be implanted at variable depths ranging from 200 to 700 microns in 100 micron steps to allow customized treatment of keratoconus, stromal corneal opacities and corneal oedema.

CE Mark approval in Europe, but not FDA approved; Case studies in USA

Expert: Alternative sources for corneal tissue needed in transplantation are important. Expert: Innovative and creative methods to generate new artificial cornea. An answer to hundred of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection. Expert: Insufficient detail to assess how this would work. Needs proof of concept. https://ascrs.confex.com/ascrs/15am/webprogram/Paper10658.html

33 Artificial cornea, RHCIII-MPC implants

Corneal transplantation

Developer: Linköping University - Integrative Regenerative Medicine Centre (Sweden) Description: RHCIII-MPC implant consisting of RHCIII (8% wt/vol; from FibroGen, Inc, San Francisco, USA), MPC (4% wt/vol) and poly(ethylene glycol) diacrylate (1.37% wt/vol) for anterior lamellar corneal transplantation. RHCIII-MPC implants can be cut by femtosecond laser to complement implant and host surgical beds for subsequent tissue welding.

Case studies, n=3; Ukraine; previously RHCIII component alone completed phase I

Expert: Alternative sources for corneal tissue needed in transplantation are important. Expert: Innovative and creative methods to generate new artificial cornea. An answer to hundreds of cases where human corneal transplantation is not possible due to severe ocular surface disease or very high risk of corneal graft failure and rejection. Expert: needs further evidence of efficacy. http://onlinelibrary.wiley.com/doi/10.1111/cts.12293/full

55

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

34 Novel keratoprosthesis

corneal damage, severe

Developer: University Of Miami (USA) Description: The keratoprosthesis comprises a support made of titanium which is textured to enable improved soft tissue adhesion. This results in less extrusion and corneal thinning, than previously known keratoprostheses for treating severely damaged cornea. It also obviates many of the complications and drawbacks of known keratoprostheses. For instance, use of the present keratoprosthesis presents no oral defects (i.e. MOOKP).

Phase N/A; no info

Expert: New corneal replacement technologies are needed. Expert: but no available data to substantiate claims. http://www.google.com/patents/WO2014039495A1?cl=en

Biometry

35 Biometry device, Galilei G6, intended to be used during ophthalmic procedures

Corneal disease Developer: Ziemer Ophthalmic Systems AG (Switzerland) Description: Galilei G6 is a biometry device which integrates tomography, topography and biometry intended to be used during ophthalmic procedures. It is designed to measure axial and intraocular distances in one exam session. It is based on optical coherence. It features dual scheimpflug high definition corneal power, pachymetry and posterior surface maps. It helps in IOL calculation through lens thickness. It reduces realignment errors. Its speed

In approval process

Expert: Useful but not novel. Expert: A current biometry method does not integrate so many details about cornea. Additionally allowing for more accuracy in IOL positioning. Expert: Based on previous Galilei device. May prove to be more specific that current standards for detection of keratoconus http://galilei.ziemergroup.com/galilei-g6.html

56

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

is 60 images in one second, axial length of14 to 40 mm, central corneal thickness of 250 to 800 µm, anterior chamber depth of 1.5 to 6.5 mm, lens thickness of 0.5 to 6.5 mm, keratometry of 25 to 75 D and pupilometry of 0.5 to 10 mm.

Contact lens, osmotic (absorbent)

36 Contact lens, Hyper CL (hyperosmotic)

Corneal oedema; Corneal oedema after cataract surgery

Developer: Eye-Yon Medical (Israel) Description: Hyper-CL is a hyperosmotic disposable contact lens. The unique structure of the lens enables extraction of fluid from the corneal stroma by osmosis from the corneal oedema, combined with increased evaporation over the lens surface. The dual base curve combined with the groove and the holes inside the lens creates a micro-environment above the cornea centre that holds fluid with high ionic concentration, and will increase the contact time of any drop applied onto the lens surface. It is replaced every two weeks.

CE marked in Europe and currently available at one NHS institution and in commercialisation process

Expert: Useful in cases where endothelial transplantation is not possible or in waiting for such procedures. Expert: Concerns about safety. Expert: No indication for what this would be used or what benefits it offers over current therapies. www.eye-yon.com

37 Contact lens, soft, Hyper-CLTM lens

Corneal oedema Developer: Kaplan Medical Center, Rehovot (Israel); Barzilai Medical Center, Ashkelon (Israel); EyeYon (Israel)

Israel, 12 eyes; CE approved

Expert: Useful in cases where endothelial transplantation is not possible or in waiting for such procedures. Expert: RCT against standard treatment required.

57

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Description: Hyper CLTM - Hyperosmotic contact lens extracts fluids by osmosis from the corneal edema. It creates a cavity above the center of the cornea that can store hypertonic drops – a sodium chloride solution for the eye that is used to draw water out of swollen corneas. The drops are gradually released throughout the day, allowing for relief and improved treatment that may, help delay or alleviate the need for a corneal transplant.

http://dx.doi.org/10.1111/aos.12582

Contact lens, scleral/corneoscleral

38 Artificial tear reservoir, PROSE (Prosthetic Replacement of Ocular Surface Ecosystem) scleral lens prosthetic device

Distorted cornea and ocular surface disease

Developer: BostonSight (USA). Description: PROSE is a transparent dome, filled with a sterile saline solution that serves as an artificial tear reservoir, providing constant lubrication to the eye, and allowing oxygen to reach the cornea. The device is composed of gas permeable material which creates a smooth surface over the damaged cornea. PROSE devices fit under the eyelids, vaulting the damaged cornea and resting on the sclera, Worn during waking hours.

USA FDA approved, available to BostonSight Network Clinics in USA, company plan additional launches in the UK and elsewhere in the next 3 years

Expert: There is a need for this in difficult cases. Expert: Unique principle, Promising in dry eye, corneal surface disease http://www.bostonsight.org/PROSE-treatment/About-PROSE

39 Contact lens, Scleral,

Keratoconus and irregular

Developer: Tokyo Women's Medical University (Japan); Taiwan Macro

JPRN-UMIN00001357

Expert: There is a need for this in difficult cases. Expert: Unique principle, Promising in dry eye, corneal

58

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

therapeutic, filled with saline solution and daily control with fluid exchange

astigmatism after refractive surgery, refractory to conventional therapy

Vision Corp., (Taiwan) Description: HiClear, Fluid-ventilated, gas-permeable, corneoscleral contact lenses.

4, Japan, n=20; Taiwan, n=8 (12 eyes)

surface disease http://www.sciencedirect.com/science/article/pii/S2211505614000064

40 Contact lens, Scleral, therapeutic, filled with saline solution and daily control with fluid exchange

Ocular surface burns, severe

Developer: Microlens (The Netherlands) Description: Misa® Scleral lenses rest on the sclera outside of the limbal area.

Algeria; Case studies, n=4

Expert: There is a need for this in difficult cases. Expert: Unique principle, Promising in dry eye, corneal surface disease http://eposter.europa-organisation.com/2015/eclso/index/slide/abstract/2

Corneal graft delivery device

(to allow insertion of corneal tissue through smaller incisions to reduce damage to the limbal area)

41 EndoGlide Ultrathin graft insertion device

Corneal endothelium disease

Developer: Lions Eye Institute, Perth (Australia) Description: Endothelial keratoplasty has largely replaced penetrating keratoplasty as the preferred technique to selectively replace diseased corneal endothelium. Descemet's stripping automated endothelial keratoplasty (DSAEK) is the most common type of endothelial keratoplasty performed worldwide. One of the challenges in DSAEK is the insertion of the donor lenticule into

Australia; development stage unknown

Expert: There are many devices now available for DSAEK http://www.networkmedical.co.uk/ophthalmic_tan-endoglide-ultrathin.html

59

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

the eye using a method so as to minimize endothelial cell loss. With the trend towards using thinner DSAEK tissue and Descemet membrane endothelial keratoplasty, there are increasing challenges in inserting and manipulating even more delicate tissue. The EndoGlide Ultrathin will enable easier insertion of thinner DSAEK tissue.

42 EndoInjector (device for delivery of corneal graft)

Corneal disease Developer: KeraMed Inc. (USA) Description: The EndoInjector is a minimally-invasive, simple, one handed use device intended to be used during Descemet's stripping endothelial keratoplasty (DSEK) procedures. It is designed to enable delivery of a corneal graft. It can deliver an 8 to 9mm DSEK graft through a clear corneal incision as small as 3.2 mm. It produces only about 13% endothelial cell loss.

In approval process

Expert: There are many devices now available for DSAEK http://www.keramed.com/endoinjector/

Device delivering microwaves to the cornea

43 Keraflex Microwave System (non-incision device used to flatten protruding cone)

Keratoconus Developer: Avedro, Inc. (USA) Description: Refractive Surgery; Keraflex Microwave System is a microwave-based, non-incision device. It is designed to flatten the protruding cone of keratoconus without the removal of tissue and make the

Approved, CE marked ; clinical trials currently underway

Expert: There is a need for better treatments for progressive keratoconus Expert: This treatment has been discontinued in most eye centres due to lack go long term efficacy. Expert: Subsequent cross liking may provide stability of treatment that was absent with previous Keraflex device.

60

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

irregular cornea smoother whilst preserving the biomechanical integrity of the cornea and the ability to effect refractive changes. A single low-energy microwave pulse lasting less than 1 second is applied to the cornea using a dielectrically shielded microwave emitter, which noninvasively contacts the epithelial surface. Through capacitive coupling, the single pulse raises the temperature of the selected region of corneal stroma to approximately 65°C, shrinking the collagen, and forming a toroidal lesion in the upper 150 µm of the stroma below Bowman’s membrane. The treatment is then followed by CXL to “lock in” the flattening effect.

Patient focus group: ‘the mention of microwaves put people off’. http://avedro.com/press-releases/keraflex-keratoconus-treatment-study-begins-in-us/

Gel to cushion and protect corneal tissue during surgery

44 Intraocular lens, Acurus SH

Corneal transplantation

Developer: EyeKon Medical, Inc. (USA) Description: Acurus SH is a sodium hyaluronate based clear, sterile and non-pyrogenic device intended to be used in intraocular surgery. It is designed to create and maintain the space in patient's eye, manipulate intraocular tissue and protect the corneal endothelium during posterior and anterior segment intraocular

Clinical, estimated approval - Oct 2016, estimated launch - Jan 2017

Expert: There are viscoelastics currently available. Expert: Novel in protecting corneal endothelium http://eyekonmedical.com/viscoelastic-2/

61

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

surgery. It is temporarily injected behind the cornea prior to surgey and removed afterward. It is designed to create and maintain the space in the patient's eye and protect the cornea during surgery. Its cohesive characteristics are especially suited for phacoemulsication since its higher viscosity enables it to effectively maintain space and gently manipulate delicate intraocular tissue. It will be available in a range from 1 percent to 3 percent with a possible viscosity range of 2,000 cPs to greater than 75, 000 cPs. It is delivered through glass syringe with a cannula.

45 Intraocular lens, Cirrus Biogel SH

Corneal transplantation

Developer: EyeKon Medical, Inc. (USA) Description: Cirrus Biogel SH Viscoelastic is a sodium hyaluronate based clear, sterile and non-pyrogenic device intended to be used in intraocular surgery. It is designed to create and maintain the space in patient's eye, manipulate intraocular tissue and protect the corneal endothelium during posterior and anterior segment intraocular surgery. It is temporarily injected behind the cornea prior to surgery and removed afterward. It is

Clinical, estimated approval - Feb 2017, estimated launch - May 2017

Expert: There are viscoelastics currently available. Expert: Novel in protecting corneal endothelium http://eyekonmedical.com/cirrus/

62

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

designed to create and maintain the space in the patient's eye and protect the cornea during surgery. Its cohesive characteristics are especially suited for phacoemulsication since its higher viscosity enables it to effectively maintain space and gently manipulate delicate intraocular tissue. It will be available in a range from 1 percent to 3 percent with a possible viscosity range of 2,000 cPs to greater than 75, 000 cPs. It is delivered through glass syringe with a cannula.

Intraocular lens

46 Intraocular lens, Posterior Chamber Phakic IOL (toric implantable collamer lens (TICL))

Keratoconus with myopia

Developer: Apollo Hospitals, Hyderabad (India); Tabriz University of Medical Sciences (Iran) Description: Phakic IOLs (intraocular lenses) are clear implantable lenses that are surgically placed either between the cornea and the iris or just behind the iris, without removing the natural lens. Phakic lenses enable light to focus properly on the retina for clearer vision without corrective eyewear. Phakic IOLs are an alternative to LASIK and PRK eye surgery for correcting moderate to severe myopia, and in some cases produce better and more predictable

India, n=32 (48 eyes), n=32; IRCT2012063010143N1, Iran, n=20

Expert: Better management in patients with keratoconus is needed. Expert: Not new https://ascrs.confex.com/ascrs/15am/webprogram/Paper16638.html

63

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

vision outcomes than laser refractive surgery and are currently indicated for the correction of moderate to severe myopia.

47 Intraocular lens, pseudophakic

Keratoconus, nonprogressive, and pellucid marginal degeneration and contact lens intolerance

Developer: Ankara University Faculty of Medicine - Department of Ophthalmology (Turkey) Description: Pseudophakic (removal of lens, clear or with cataract) intraocular lens implantation for visual correction.

Turkey; n=11 (15 eyes)

Expert: Better management in patients with keratoconus is needed. https://ascrs.confex.com/ascrs/15am/webprogram/Paper12609.html

48 Intraocular lens, Toric one-piece aspheric IOL (intraoperative lens), Tecnis®

Corneal astigmatism

Developer: Abbott Laboratories (USA) Description: The TECNIS® 1-Piece IOL provides ease of implantation (reduced center thickness for slim lens profile facilitates implantation), bag-friendly, coplanar delivery and a proprietary surface treatment for ease of unfolding (polished haptic loops enable controlled, gentle unfolding in capsular bag).

CE marked in Europe

Expert: There are many toric lenses already available. Patient focus group: The intraocular lens sounds good but there was concern that putting a hole in the eye would add to the risk. This was viewed as an option of last resort. http://www.tecnisiol.com/us/physician/index

Intrastromal corneal ring/inlay

49 Intrastromal corneal ring segments implantation at penetrating keratoplasty

Corneal graft astigmatism

Developer: Universitäts Augenklinik (Germany) Description: Graft astigmatism is a major problem after corneal transplantation. Intrastromal corneal ring after penetrating keratoplasty is evaluated as a corrective procedure.

DRKS00001030; Germany; n=20

Expert: Intracorneal rings are already available, including before cross-linking. http://www.drks.de/DRKS00001030

64

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Ocular bandage

50 Bandage, ocular, hydrogel liquid ocular (Ocuseal)

Prevent air leak from the corneal incisions in Descemet's membrane endothelial keratoplasty (DMEK)

Developer: Beaver-Visitec International (USA) Description: OcuSeal®, a hydrogel liquid ocular bandage, is a fully synthetic product developed to provide a protective hydrogel film barrier while stabilizing ocular wounds. It is designed to promote healing by protecting the corneal incision from eyelid trauma. It is intended to maintain air fill in the anterior chamber by securing corneal incisions in DMEK.

UK, n=12, 12 eyes; CE marked in 2008; not FDA approved

Expert: This has other novel uses other than the one described. http://www.escrs.org/abstracts/details.asp?confid=21&sessid=711&type=Poster&paperid=25213

Surgical device for creating incisions in the cornea

51 Ocular Surgical Tool (microscopic tool to remove scars from cornea)

Corneal disease Developer: Nanophthalmics (USA) Description: Ocular Surgical Tool is a microscopic tool intended for ocular surgery, based on Etched-Glass-Technology. It is designed to manipulate tissue using etched glass materials to remove scar tissue from the eyes. Its etched-glass material has microscopic spikes which are 80 microns long and works like a bed of nails.

In approval process, estimated approval - Apr 2016, estimated launch - July 2016

Expert: Intra-operative devices need to be developed. Expert: Difficult to know how this would work

65

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Drugs

Antibacterial

52 Honey drop, topical

Corneal ulcer Developer: Shiraz university of medical sciences (Iran) Description: A drop of topical honey drop 70% (manufactured by pharmacologic centre of Shiraz university of medical sciences) every 6 hours.

IRCT2015020120892N1; Phase N/K; Iran; n=50

Expert: Honey is known to have anti-microbial properties. Expert: more studies needed. Expert: Could provide evidence for anecdotal claims. Patient focus groups: “there was some fascination about the use of honey with participants feeling they would prefer something natural rather than chemicals but a fear that it may clog tear ducts”. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2015020120892N1

Antifungal

53 Voriconazole, topical

Keratitis, acanthamoeba-positive epithelial

Developer: Leicester Royal Infirmary Ophthalmology Department (UK) Description: Voriconazole is a triazole antifungal medication. It has been shown to be effective in treating resistant Acanthomeba keratitis.

UK; n=5 Expert: The role of voriconazole in acanthamoeba needs to be clarified. Expert: small sample, not enough evidence. Expert: Could be helpful in resistance cases. http://www.eucornea.org/barcelona-2015/poster-abstracts-barcelona-2015?sessiom=54

Anti-inflammatory

Patient focus groups: There was interest in treatments which reduced inflammation as participants felt instinctively that must be a logical and sensible thing to do.

54 Omaveloxolone (ABT-RTA 408; RTA-408)

Corneal post-operative inflammation and corneal endothelial cell

Developer: AbbVie (USA); Reata Pharmaceuticals, Inc. (USA) Description: Omaveloxolone is a synthetic triterpenoid that acts by suppression of oxidative stress and

NCT02128113; Phase 2; USA; n=304; completed; study

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. https://ClinicalTrials.gov/show/NCT02128113

66

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

loss inflammation, specifically via activation of the cytoprotective transcription factor Nrf2. Omaveloxolone ophthalmic suspension is administered one drop applied twice daily for a maximum of 28 days.

completion Feb 2015

55 Thymosin beta-4 (thymosin ß4; RGN 259; GBT-201; GBT201; Tß4; TB4; RGN-259; RGN-352; RGN-457)

persistent corneal epithelial defect

Developer: University of Maryland School of Medicine - Department of Ophthalmology and Visual Sciences (USA) Description: Tß4 has been demonstrated to promote corneal wound re-epithelialization, diminish inflammation, and inhibit apoptosis. Its most unique property is its anti-inflammatory effects. Single dose of 4 eye drops.

USA; FDA compassionate use

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Could be useful if efficacious. http://www.sciencedirect.com/science/article/pii/S1319453414000770

Antimetabolite

56 Chemotherapy, topical (topical 5-FU 1% or mitomycin-C (MMC) 0.04%)

Ocular surface squamous neoplasia, diffuse

Developer: South Australian Institute of Ophthalmology (Australia) Description: Diffuse OSSN, defined as a lesion extending over five or more limbal clock hours or by extensive central or paracentral corneal spread, is treated with either topical 5-FU 1% or mitomycin-C (MMC) 0.04%. 1% topical 5-FU 4 drops daily for either four to seven days on/30 days off or continuously for three to four

Australia; 38 eyes

Expert: There are better less toxic agents available (interferon drops). Expert: Useful mode of treatment. http://dx.doi.org/10.1111/ceo.12377

67

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

weeks. 0.02-0.04% MMC given as eye drops four times daily, with cycles of one to two weeks “on” and one to two weeks “off.”

Antisense or RNA interference

57 Aganirsen, GS101 eye drops; GS-101 (antisense oligonucleotide)

Keratitis or keratouveitis infectious (of bacterial, viral (e.g. herpes), or traumatic (e.g. alkali burns) origin) -related neovascularisation and or corneal graft rejection

Developer: Les Laboratoires CTRS; Gene Signal Description: Aganirsen is an antisense oligonucleotide against the insulin receptor substrate-1 (IRS-1). Antisense oligonucleotides are short, synthetic oligonucleotides which are complementary in sequence and function by specific hybridisation to their cognate gene product (mRNA), inducing inhibition of gene expression. IRS-1 is known to be over-expressed in pro-angiogenic conditions, and by reducing the over-expression of IRS-1 associated with pathological neovascularisation, aganirsen regulates both the expression of angiogenic growth factors and inflammatory cytokines. Aganirsen is administered via twice daily eye drops at a total dose of 86µg daily for 2-6 months depending on the spread and degree of pathological

EUCTR2008-005388-33-DE, Phase 3, France Germany Switzerland, n=70, not recruiting; EUCTR2004-005015-29-DE, Phase 2, Germany, n=100, not recruiting

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: novel approach to stop formation of corneal neovscularisation. Expert: Important clinical application. http://www.ncbi.nlm.nih.gov/pubmed/24811963

68

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

neovasularisation.

58 Nexagon; CODA001

Chemical and thermal ocular injury

Developer: University of Auckland, New Zealand National Eye Centre (New Zealand); CoDa Therapeutics (USA) Description: Nexagon is a anticonnexin natural oligonucleotide. It down-regulates the key gap junction protein connexin43 to dampen inflammatory responses and enhance healing. In each case the eye was prepared with local anaesthesia, either topical or subconjunctival. The gel (2μM concentration) was injected beneath an amniotic membrane graft sutured to the corneal surface OR the gel at 20μM was applied under a 14-mm corneoscleral bandage contact lens. The eyelids were then closed and padded.

New Zealand; compassionate use

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Little available data. http://link.springer.com/article/10.1007%2Fs00232-012-9460-4

59 SYL1001; SYL-1001; SYL1001

Ocular Pain associated with dry eye syndrome

Developer: Sylentis, S.A. Description: SYL 1001 is based on the gene silencing technology of RNA interference. The compound is designed to target the capsaicin receptor, TRPV1, a nocioceptor which mediates inflammation and pain. The silencing of TRPV1 using siRNA may lead to reduced levels of expression of TRPV1, thus providing a potential

NCT02455999; Phase 2; Spain, Estonia; n=66; completed; Mar 2016

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: corneal pain management in dry eye disease. Expert: Difficult to see how this could treat ocular pain. Perhaps helpful in corneal discomfort. Patient focus groups: Although pain relief is important, as one comment suggested fully removing pain can be a worrying option:’I would avoid drugs the ‘prevent pain’ like SYL1001 because I think some pain is vital to

69

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

therapy for the treatment of ocular pain. SYL1001 eye drops (dose not disclosed) administered for 10 consecutive days

highlight that something is wrong’. https://ClinicalTrials.gov/show/NCT02455999

Antiseptic

60 Polyhexamethylene biguanide 0.02%, topical

Keratitis, acanthamoeba

Developer: University of Tsukuba (Japan) Description: Polyhexanide (polyhexamethylene biguanide, PHMB) is a polymer commonly used as a disinfectant and an antiseptic, it is used in contact lens disinfecting solutions. Topical administration of 0.02% polyhexamethylene biguanide is administered every 4 hours.

JPRN-UMIN000012496, n=400; JPRN-UMIN000017019, n=200; Phase N/K; Japan; not yet recruiting

Expert: This is used off license clinically. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000012496

61 Povidone-iodine, topical

Keratoconjunctivitis, Epidemic ; Superficial keratitis with conjunctivitis

Developer: Zahedan University of Medical Sciences (Iran) Description: Povidone-iodine is a broad spectrum antiseptic for topical application in the treatment and prevention of infection in wounds, as well as killing bacteria. Minims Povidone Iodine 5% w/v Eye Drops, Solution is indicated (in UK) for cutaneous peri-ocular and confunctival antisepsis prior to ocular surgery to support post-operative infection. Povidone iodine for 9 days overall. Days 1-3 every 4 hour, days 4-6 every 8 hour and days 7-9 every 12

IRCT2015021518004N2; Phase 2/3; Iran; n=60; recruiting

Expert: This is not currently used in practise but available. Expert: Could be a cheap alternative to antibiotic use. http://www.irct.ir/searchresult.php?id=18004&number=2

70

# Technology Indication Description *Stage of development

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hour. Dose undisclosed.

Antiviral

62 APD-209 Eye drops (a new trisialic acid compound)

Keratoconjunctivitis, Infectious (epidemic adenoviral)

Developer: Adenovir Pharma AB Description: APD-209 is a topical trisialic acid compound with an unknown mechanism of action but known to prevent EKC-causing adenoviruses from binding to the receptors corneal cells so preventing infection. 0.125mg/ml eye drop suspension.

NCT01977443, EudraCT2012-005694-31; Phase 2; Germany, Poland, Sweden; n=130; recruiting; study completion Dec 2016

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Treat the commonly contagious adenoviral infection of the eye Expert: Efficacy data required. https://ClinicalTrials.gov/show/NCT01977443

63 Gancyclovir (or DHPG) gel, topical 0.5%

Cytomegalovirus corneal endotheliitis and iritis

Developer: Shimane university hospital (Japan) Description: Ganciclovir is an antiviral agent. It works by blocking reproduction of the cytomegalovirus (CMV) virus. 1 drop given 8 times for severe case; 6 times for moderate cases; 4 times for mild cases tapering after improvement and stopped when PCR shows negative of CMV.

JPRN-UMIN000018977, n=10; JPRN-UMIN000012435, n=10 Phase N/K; Japan; open public recruiting

Expert: CMV keratitis is poorly understood including diagnostic tests and treatments. Expert: Drop form currently unavailable but ointment readily available. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&language=E&recptno=R000021954

Cystine antagonist

64 Cystadrops® gel (cysteamine hydrochloride (CH) eye drops; mercaptamine opthalmic;

Corneal cystine crystals in cystinosis

Developer: Quinze-Vingts National Eye Center - Department of Ophthalmology (France) Description: Without proper treatment, cystine crystals accumulate in the cornea, leading to progressive

EudraCT No: 2007-006024-35; Phase 2; France; n=8; completed

Expert: There is a need for better treatments in this rare disease. Expert: Rare disease but limited options and this one meet needs. Expert: Other agents already exist. http://dx.doi.org/10.1016/j.ymgme.2013.12.298

71

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

mercamine; 2-aminoethanethiol)

blurred vision, pain, photophobia and frequent eye infections. Cystadrops is a cystine antagonist. Administered 3 times a day for at least 1 month

Immunomodulator

65 Ciclosporin A eye drops, 0.05 and 0.1%; Vekacia; Ciclosporin, opthalmic; Nova-22007; Nova22007;

Keratoconjunctivitis, Vernal (VKC), paediatric

Developer: Santen Pharmaceuticals (Japan) Description: Ciclosporine is an immunomodulator that decreases the swelling in the eye to allow tear production. Vekacia is a topical cationic emulsion of ciclosporin A. Administered 1mg/ml 4 times a day as monotherapy. Administered 2 or 4 times a day for 4 weeks.

EUCTR2012-005060-10-HU; NCT01751126; Phase 3; United States, Croatia, France, Germany, Greece, Hungary, India, Israel, Italy, Portugal, Spain; n=168; ongoing, study completion April 2016, intended

Expert: This drug has been approved for dry eye disease but not yet for vernal. Expert: NICE supported (this might refer to NICE technology appraisal guidance [TA369] where it is indicated for dry eye disease). Expert: CsA is already known to be beneficial. This dosing regime is unique. https://ClinicalTrials.gov/show/NCT01751126

66 Ciclosporin, 2% topical

Keratitis, herpetic interstitial; keratitis and keratoconjunctivitis, herpesviral

Developer: Isfahan University of Medical Sciences (Iran) Description: Ciclosporine is an immunomodulator that decreases the swelling in the eye to allow tear production. Topical Cyclosporine 2% is administered 1 gtt (drop) every 12 hours.

IRCT2015052112724N2; Phase N/K; Iran; n=48; recruiting

Expert: The long-term role of ciclosporin for herpetic keratitis is poorly studied. Expert: NICE supported (this might refer to NICE technology appraisal guidance [TA369] where it is indicated for dry eye disease) http://www.irct.ir/searchresult.php?id=12724&number=2

72

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

67 Tacrolimus (TALYMUS ophthalmic suspension 0.1%)

Keratoconjunctivitis, Severe allergic, refractory to topical anti-allergic agents

Developer: Senju Pharmaceutical Co., Ltd (Japan) Description: Tacrolimus is an immunosuppressant, inhibiting the activation of T-cells. Because of its potent immunosuppressive effect, tacrolimus is expected to exhibit excellent therapeutic efficacy in suppressing abnormal immune responses related to allergic ocular diseases. Twice daily for 24 weeks. Dose undisclosed

JPRN-UMIN000008640; Phase N/K; Japan; n=1000; completed recruitment

Expert: This is definitely needed and novel. Expert: effective and safe treatment for refractory allergic eye disease Expert: Efficacy previously demonstrated. Further evidence useful. Patient focus group: Tacrolimus for allergic reactions would have a huge positive affect on quality of life (especially during hay fever season) because it would be easy use to relieve allergies which severely impede tolerance to contact lenses. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000008640

68 Tacrolimus 0.05%, topical

Corneal graft rejection, acute endothelial

Developer: Tehran University of Medical Sciences, Farabi Eye Hospital (Iran) Description: Tacrolimus is an immunosuppressant, inhibiting the activation of T-cells. Topical tacrolimus 0.05% drop every 6 hours in addition to medication until resolution of rejection, adjunctive to conventional steroid therapy

IRCT2014040617088N1; Phase N/K; Iran; n=60; recruiting

Expert: This is definitely needed and novel. Expert: Important study and results could change current management of corneal graft rejection. Expert: Efficacy previously demonstrated. Further evidence useful. http://www.irct.ir/searchresult.php?id=17088&number=1

Nicotinic receptor antagonist

69 RPI-MN; Pepteron; alpha-cobratoxin

Keratitis, herpetic Developer: Nutra Pharma (USA) Description: RPI-MN (Pepteron) is a chemically-modified alpha-cobratoxin, a poison extracted from the venom of the Thailand cobra. Chemical modification eliminates its poisonous effect. It is a nicotinic acetylcholine

N/K; Phase 2 planned; Phase N/K

Expert: New anti-viral treatments are needed. Expert: Evidence of efficacy exists. http://www.nutrapharma.com/corporate_overview/presentations/NPHCPresentation.pdf

73

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

receptor antagonist and interferon gamma stimulator and is a potential treatment for viral infections. RPI MN contains anticholinergic peptides that antagonise the effects of the nicotinic acetylcholine receptor (AchR). Previous phase 2, dosing employed 0.2cc ramping daily by 0.1cc up to 1cc given by intramuscular injection (systemic).

Peroxisome proliferator activated receptor δ (PPARδ) agonist

70 fonadelpar; NPS-005; SJP 0035 ophthalmic solution

Corneal injuries, Corneal epithelial disorders, Moderate to Severe

Developer: Senju Pharmaceutical Co., Ltd. (Japan) Description: fonadelpar is an ophthalmic solution to promote corneal epithelial wound healing in patients with corneal epithelial disorders. 1 drop in the affected eye(s) given 4 times daily for 4 weeks.

NCT02104388; Phase 2; USA; n=88; ongoing; study completion Dec 2015, planned

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: promote healing in severe cases of persistent epithelial defect. Expert: Could be useful for non-healing ulcers. https://ClinicalTrials.gov/show/NCT02104388

Pesticides

71 Acaricide, biodegradable (to kill mites, Demodex folliculorum)

Keratoconjunctivitis caused by the ectoparasite Demodex

Developer: Laboratorios Procaps S.A (Colombia) Description: A pesticide that kills ticks and mites. Before treatment, all participants have gauzes presoaked in saline solution applied to their eyes (when closed) for five minutes; this allows greater penetration of the product being applied. A local

ISRCTN63299516; Phase N/K; Colombia; n=158; completed

Expert: New treatments for dry eye disease are needed. Expert: Demodex is not uncommon cause of blepharitis, there is a lack of effective therapies. Expert: Safety and efficacy data required. Patient focus groups: Acaricide is also a pesticide which leads people to dismiss it immediately as an option. http://isrctn.com/ISRCTN63299516

74

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

anaesthetic is also applied to each eye. A gauze moistened with either the placebo or intervention formation is applied to the eyelid and eyelashes of each participant, replacing the gauze with a clean one once debris has been seen on the gauze. The procedure is complete once no more debris can be seen on the gauze.

Synthetic or recombinant biological molecules (Proteins, peptides, or polysaccharide)

72

Calcicol eye drops (Cacicol 20 eye drops; RGTA; RGTA OTR 4120; T4020)

Corneal thinning, progressive

Developer: Medical University of Silesia, University Center of Ophthalmology and Oncology - Department of Ophthalmology (Poland) Description: CACICOL® regenerating agent family (or RGTA). These agents are used for matrix therapy (or corneal matrix repair therapy). It acts as a scaffold. Its matrix structure permits the fixation and the protection of the components involved in the tissue regeneration process. It is currently indicated for chronic corneal wound healing, such as persistent epithelial defects and persistent corneal dystrophies with associated pain.

Poland; No info Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Unique in its mechanism of action. Expert: No info. http://www.escrs.org/istanbul2015/programme/posters-details.asp?id=22723

73 Keratitis, chronic neurotrophic;

Developer: Laboratoires Thea (France); Quanta Medical

NCT01794312; Phase 3; France;

Expert: The area of novel biologics for the cornea is important and will develop considerably over the

75

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

corneal ulcer Description: CACICOL® regenerating agent family (or RGTA). These agents are used for matrix therapy (or corneal matrix repair therapy). It acts as a scaffold. Its matrix structure permits the fixation and the protection of the components involved in the tissue regeneration process. It is currently indicated for chronic corneal wound healing, such as persistent epithelial defects and persistent corneal dystrophies with associated pain. Administered 1 drop 4 times per week.

n=124; recruiting; study completion Mar 2017

following decade. Expert: unique in its mechanism of action https://ClinicalTrials.gov/show/NCT01794312

74 Keratoconus Developer: Erciyes University School of Medicine (Turkey) Description: CACICOL® regenerating agent family (or RGTA). These agents are used for matrix therapy (or corneal matrix repair therapy). It acts as a scaffold. Its matrix structure permits the fixation and the protection of the components involved in the tissue regeneration process. It is currently indicated for chronic corneal wound healing, such as persistent epithelial defects and persistent corneal dystrophies with associated pain. Dose undisclosed.

Turkey; n=60 Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: unique in its mechanism of action https://www.regmednet.com/users/1034-alexandra-thompson/posts/3827-new-drug-boosts-repair-of-cornea-following-surgery

76

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Heparin sulphate proteoglycan mimetic

75 Persistent Corneal Epithelial Defects (PEDs)

Developer: Medical University of Warsaw-Department Ophthalmology (Poland) Description: CACICOL® regenerating agent family (or RGTA). These agents are used for matrix therapy (or corneal matrix repair therapy). It acts as a scaffold. Its matrix structure permits the fixation and the protection of the components involved in the tissue regeneration process. It is currently indicated for chronic corneal wound healing, such as persistent epithelial defects and persistent corneal dystrophies with associated pain. Instilled (volume unknown) once or twice a week for over one month.

Poland; n=4 Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: unique in its mechanism of action http://www.eucornea.org/london-2014/london-2014-posters?sessiom=39

76 Coenzyme Q10 eye drop, topical

Corneal ulcer, refractory

Developer: Erciyes University School of Medicine - Department of Ophthalmology (TURKEY) Description: CoQ10 is an endogenous enzyme cofactor involved in electron transport in the mitochondria and is thought to be capable of preventing programmed cell death or apoptosis. CoQ10 eye drops were added to the existing therapies as an adjuvant

Turkey; n=6 Expert: Unclear basic science behind this and maybe other more important corneal uses for this. Expert: Study too small. Not RCT. http://www.ncbi.nlm.nih.gov/pubmed/26783983

77

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

agent. 77 DE-105; DE105;

RU-105; RU105 (ophthalmic solution)

Persistent corneal epithelial defect

Developer: Sucampo Pharmaceuticals (Japan); R-Tech Ueno Description: DE-105 is a neurotrophic factor peptide, which contains the sensory nerve transmitter substance P and insulin-like growth factor-1. Administered as an ophthalmic solution, dose not disclosed.

NCT00988494; Phase 2 completed; Japan; n=45; Phase 3 planned

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Unique in treating neurotrophic cornea Expert: Could be useful for non-healing ulcers. http://clinicaltrials.gov/ct2/show/NCT00988494

78 RGN-259 (Thymosin beta-4; thymosin ß4; GBT-201; GBT201; Tß4; TB4; RGN 259)

Keratitis, neurotrophic; Keratopathy, neurotrophic

Developer: RegeneRx (USA) Description: RGN-259 is a synthetic version of the 43-amino-acid peptide thymosin ß4 (TB4), an MMP-9 and MMP-1 modulator that is a wound-healing agent. Tβ4 alleviates the signs and symptoms of dry eye by promoting stem cell recruitment and cell migration, reducing inflammation and apoptosis, enhancing cytoprotection, and promoting gene expression.

NCT02600429; Phase 3; USA; n=46; recruiting

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Promising. https://ClinicalTrials.gov/show/NCT02600429

79 rhNGF (Recombinant human nerve growth factor; Rh-NGF) eye drops

Keratitis, neurotrophic (stage 2 and 3)

Developer: Dompe SpA (Italy) Description: Recombinant human nerve growth factor (NGF) that targets two receptors, p75NTF and TrkA. NGF is essential for the survival and growth of sympathetic and sensory neurons, as well as the differentiation of neurons in the central nervous system. The biological effects of NGF

CCRN 2093 (Neurotrophic Keratitis); 14298; Phase 2; Europe; n=48

Expert: The area of novel biologics for the cornea is important and will develop considerably over the following decade. Expert: Previous evidence has shown efficacy. http://www.businesswire.com/news/home/20151202006109/en/rhNGF-Domp%C3%A9-Biotech-Molecule-Treatment-Neurotrophic-Keratitis

78

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

are mediated by activation of NGF receptors that are expressed on the anterior segment of the eye (iris, ciliary body, lens, cornea and conjunctiva). In the phase I/II clinical trial, rhNGF is administered as either a 10μg/ml or 20μg/ml eye drop solution, at one drop six times daily.

Synthetic tears

80 Hypertonic ointment

Corneal erosion syndrome, Recurrent (RCES)

Developer: University Hospital Coventry and Warwickshire (UK) Description: RCES is associated with abnormal adhesion complexes between corneal epithelial basement membrane and underlying stroma. Epithelial oedema induced by hypotonicity of tears during sleep further weakens adhesion complexes, increasing the risk of epithelial cell avulsion on awakening. Hypertonic ointments instilled before bedtime, in addition to having a lubricating effect, creates an osmotic gradient to counteract the epithelial oedema induced during eyelid closure. Sodium chloride 5% ointment used before bedtime for 6 months.

UK; n=52 Expert: New treatments for poor epithelial healing are needed. Expert: May address a common problem. Royal College of Ophthalmologists Annual Meeting

81 Therapeutic ocular surface medium (TOSM)

Persistent corneal epithelial defect

Developer: Moorfields Eye Hospital (UK) Description: Ocular surface medium

UK; n=10, 11 eyes

Expert: This is novel but has issues of GMP which will make it expensive to use. Expert: Same effect of serum drops that can be

79

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

(TOSM) is a potential physiological tear replacement therapy which unlike autologous serum, has the potential to be easily manufactured and widely available. It is a cell culture medium Therapeutic Ocular Surface Medium that contains EGF, acidic FGF and vitamin C (ascorbic acid-2-phosphate) along with proteins, amino acids, vitamins, antioxidants, carbohydrate, lipid, electrolytes, organic components, and therapeutic agents. It has the same physical properties of tears including pH and osmolality. Dose for PCED not known, one drop of TOSM was applied 8 times a day (for dry eye)

manufactured. Expert: Could provide a cheap alternative to serum. http://www.ncbi.nlm.nih.gov/pubmed/24335180

Procedures

Biological bandage

82 Anterior capsule of human crystalline lens, non preserved

Corneal epithelial defects and Moorens ulcer, non-healing

Developer: Karnataka Institute of Medical Sciences (India) Description: The anterior capsule retrieved during routine extracapsular cataract extraction in another patient is directly placed on the recipient cornea of a patient with epithelial defect. The Lens capsule acts as a collagen shield and aids in the healing of the epithelial defect.

CTRI/2012/03/002484; Phase N/K; India; n=25

Expert: Novel use of lens capsule. Expert: readily available. could be beneficial if shown to be helpful. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2012/03/002484

80

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

CXL, standard

83 Collagen cross-linking, corneal

Keratoconus, paediatric

Developer: Moorfields Eye Hospital NHS Foundation Trust (UK); Royal Victorian Eye and Ear Hospital (Australia); Minamiaoyama Eye Clinic, Tokyo (Japan) Description: Standard CXL but used in children.

ACTRN12611001062910, Phase N/K, Australia, n=20, Recruiting ; JPRN-UMIN000014937, Phase N/K, Japan, n=30, Open public recruiting

Expert: The efficacy of CXL in children is not realised yet. There is a UK multi-centre study to determine this. Expert: it is critical to know whether current CXL protocols are effective in children EME Project: 14/23/18

84 Collagen cross-linking, corneal

Keratopathy, bullous

Developer: The Chinese University of Hong Kong (Hong Kong); University of Melbourne (Australia) Description: Standard CXL instead of transplant to alleviate discomfort and pain.

Phase N/A; no info

Expert: Novel use of CXL http://www.ncbi.nlm.nih.gov/pubmed/24807064

CXL, to treat infection

85 Collagen cross-linking, corneal

Corneal ulcer, infectious or bacterial

Developer: Tabriz University of Medical Sciences - Ophthalmology department (Iran); Shiraz University of Medical Sciences; Khalili eye hospital (Iran) Description: Corneal CXL on recalcitrant infectious corneal ulcers without appropriate response to maximal conventional topical and subconjunctival antibiotics whose cornea are not severely thin and do

IRCT201105074166N3, n=10, Phase N/K, Iran; IRCT2014101919581N1, n=32, Phase N/K, Iran

Expert: There is an international study underway to assess this. Expert: Promising in treating resistant and persistent infectious keratitis Expert: but RCT data would be useful. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201105074166N3

81

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

not have a history of herpetic keratitis or bacterial ulcers.

86 Collagen cross-linking, corneal

Keratitis, bacterial Developer: Örebro University Hospital (Sweden) Description: In CXL a photo-activation of riboflavin is used, which is also used in Pathogen Inactivation Therapy in transfusion medicine. Several groups have presented treated ulcers and cases of infectious keratitis successfully treated with CXL.

ISRCTN21432643; Phase N/K; Sweden; n=20; completed

Expert: There is an international study underway to assess this. Expert: Promising in treating resistant and persistent infectious keratitis Expert: but RCT data would be useful. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN21432643

87 Collagen cross-linking, corneal with UV pulsed beam (30 mW/cm2 for 8 minutes)

Keratitis, microbial

Developer: Nethradhama Superspeciality Eye Hospital (India) Description: In pulsed light accelerated corneal collagen crosslinking (pl-ACXL) 8 minutes (1.5 sec. on/1.5 sec. off) of UV-A exposure at 30 mW/cm2 with an energy dose of 7.2 J/cm2 is given.

CTRI/2015/07/006000; Phase N/K; India; n=20

Expert: There is an international study underway to assess this. Expert: Promising in treating resistant and persistent infectious keratitis Expert: but RCT data would be useful. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2015/07/006000

88 Collagen cross-linking, corneal with photoactivated riboflavin (PACK-CXL)

Keratitis, Infectious (bacterial and fungal), advanced, with corneal melting

Developer: Cornea Clinic of the Research Institute of Ophthalmology (Egypt); University of Geneva (Switzerland) Description: It has been shown that CXL demonstrates excellent antimicrobial efficacy against a variety of common pathogens in vitro.

Phase N/A; Egypt; n=40 (n=21 active vs n=19 control)

Expert: There is an international study underway to assess this. Expert: Promising in treating resistant and persistent infectious keratitis https://ascrs.confex.com/ascrs/15am/webprogram/Paper13918.html

89 Collagen cross-linking, corneal, adjunctive

Keratitis, microbial

Developer: Royal Victorian Eye and Ear Hospital (Australia) Description: conventional treatment

ACTRN12611000189921; Phase N/K; Australia;

Expert: There is an international study underway to assess this. Expert: Promising in treating resistant and persistent

82

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

plus corneal CXL. n=298; Recruiting

infectious keratitis Expert: but RCT data would be useful. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ACTRN12611000189921

CXL, without debridement

90 Collagen cross-linking, corneal with a mechanical disruption of epithelium (not debridement)

Keratoconus. paediatric

Developer: Queen Victoria Hospital (UK) Description: Corneal CXL using a technique where the corneal epithelium is physically disrupted but not removed.

Phase N/A; n=25;

Expert: Need to assess crosslinking in children and non-debridement methods.

91 Collagen cross-linking, corneal, accelerated, epi-on with CCL-VARIO UV light source (18 mW/cm2 for 5 minute)

Keratoconus, progressive (adult and paediatric)

Developer: Oftalmosalud Instit de Ojos (Peru) Description (Adult and Paediatric): Accelerated epi-on (without the removal of the corneal epithelium) CXL with a pre-soak with TE-riboflavin for a 30 minutes and UV-A light exposure performed with CCL-VARIO at a power of 18 mW/cm2 for 5 minutes.

Phase N/A; 60 eyes (30 eye in each group)(adult); n=56 (34 eyes epi-on)(paediatric)

Expert: The efficacy of epithelium on CXL needs to be investigated. https://ascrs.confex.com/ascrs/15am/webprogram/Paper17610.html

92 Collagen cross-linking, corneal, epi-on using iontophoresis (for riboflavin transcorneal delivery)

Keratoconus; Keratoconus, post-refractive surgery ectasia; Keratoconus, progressive

Developer: Avedro Inc; Eye Hope Charity (UK) Description: trans-epithelial (epi-on) riboflavin/ultraviolet A corneal CXL using iontophoresis for riboflavin transcorneal delivery to halt the progression of keratoconus.

ISRCTN04451470 ; Phase N/K; UK; n=30 (ISRCTN04451470); completed

Expert: The efficacy of epithelium on CXL needs to be investigated. https://ascrs.confex.com/ascrs/15am/webprogram/Paper15282.html

83

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

CXL, of donor tissue

93 Collagen cross-linking, corneal, epi–off, using refractive stromal lenticule of another patient undergoing small incision femtosecond lenticule extraction

Keratectasias, progressive (keratoconus and post-LASIK keratectasia) with thinnest pachymetry value of <400 microns and not treatable using standard de-epithelialization techniques.

Developer: Centre For Sight, Safdarjung Enclave (India) Description: To evaluate epi–off corneal CXL using refractive stromal lenticule of another patient undergoing small incision femtosecond lenticule extraction, in patients having keratectasia with thinnest pachymetry value of less than 400 microns and not treatable using standard de-epithelialization techniques.

Phase N/A; n=5 Expert: Rehabilitation of corneas following CXL is important. https://ascrs.confex.com/ascrs/15am/webprogram/Paper10898.html

CXL, accelerated

94 Collagen cross-linking, corneal using /KXL System, VibeX, Photrexa or Photrexa Viscous

Keratoconus (mild to moderate, progressive), corneal ectasia following refractive surgery, or corneal ectasia, progressive

Developer: Avedro, Inc. Description: Accelerated CXL using VibeX Rapid™(0.1% Riboflavin, Saline, HPMC), Photrexa Viscous (riboflavin ophthalmic solution) and Photrexa (riboflavin ophthalmic solution) and higher powered UV light source (The KXL® System). VibeX Rapid™ is riboflavin formulated with no dextran to reduce corneal thinning. It has a diffusion rate of twice that of standard riboflavin. Photrexa Viscous and Photrexa are photoenhancers.

NCT01643252, NCT00674661; NCT01344187; NCT01643226; and NCT01972854; CTRI/2015/10/006263; NCT00647699; JPRN-UMIN000014719; Phase FDA approval received

Expert: Novel cross-linking agents. http://avedro.com/medical-professionals/products/riboflavin-family/vibex-rapid/

84

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

KXL System achieves accelerated CXL in just minutes by increasing the UVA light power and reducing the exposure time while maintaining the same total energy on the eye as standard CXL. Procedure: application of VibeX Rapid (vitamin B2) solution to the eye for a 10 minute pre-soak (instead of standard 30 minutes) followed by cornea exposure to higher power UVA light (power 30mW/cm2, 365nm) using the KXL® System for approximately 4 minutes (instead of standard 30 minutes).

18/04/16; New Drug Application (NDA); Phase 3 completed; Japan; n >800 (also trial using IROC-UV-X Illumination System to represent KXL, see link)

95 Collagen cross-linking, corneal with epi-off with UV pulsed beam

Keratoconus, progressive

Developer: Marmara University School of Medicine - Department of Ophthalmology (Turkey); Crowd Health Research, LTD (USA) Description: Pulsed light treatment, higher power UV-A (power 18 mW/cm2) for a shorter time, 5 minutes, alternating 1 minute of treatment with 1 minute rest for a total time of 10 minutes.

NCT02095730; Phase 3; n=80 (115 eyes) (progressive keratoconus) and n=500 (unstable corneas)

Expert: Alternative protocols for CXL need to be studied. https://ascrs.confex.com/ascrs/15am/webprogram/Paper14843.html

96 Collagen cross-linking, corneal, accelerated, epi-off (18

Keratoconus, progressive

Developer: Keio University School of Medicine (Japan); Isfahan University - medical sciences department of research and technology (Iran); Noor eye hospital (Iran)

JPRN-UMIN000011492, n=10, Japan, Phase N/A; IRCT201508072

Expert: Alternative protocols for CXL need to be studied. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000011492

85

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

mW/cm2 for 5 minute)

Description: Accelerated CXL with settings of 18 mW/cm2 UV-A for 5 minutes (total surface dose of 5.4 J/cm2) - Japan. Description: riboflavin 0.1% drop is instilled onto the cornea every 3 minutes for half an hour (a total of 10 times). Then, 3mW/cm2 UV-A irradiation at a wavelength of 370 nanometre, a width of 9 mm, and a distance of 5cm for 5 minutes, the corneal surface is rinsed with sterile balanced saline solution, a soft bandage contact lens was placed. Chloramphenicol and betamethasone eye drop will be prescribed at discharge - Iran. Description: Corneal CXL: riboflavin 0.1% for 30 minutes then irradiated with UV-A power 18 mW/cm2 for 5 minute - Iran.

3537N1, 72 eyes, Iran, Phase N/A; IRCT2013040912960N1, n=40, Iran, Phase N/A; IRCT201207244333N1, 60 eyes, Iran, Phase N/A

97 Collagen cross-linking, corneal, accelerated, UV continuous beam (30 mW/cm2 for 3 minutes)

Keratoconus and corneal ectatic conditions

Developer: Nethradhama Superspeciality Hospital (India) Description: Continuous mode accelerated CXL with a UV-A power setting at 30 mW/cm2 for 3 minutes, and energy dose of 6.6 J/cm2.

CTRI/2015/06/005926; Phase N/K; India; n=100

Expert: Alternative protocols for CXL need to be studied. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2015/06/005926

98 Collagen cross- Keratoconus Developer: Avedro, Inc. (USA) ChiCTR-ONC- Expert: Alternative protocols for CXL need to be

86

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

linking, corneal, photorefractive intrastromal (PiXL) KXL II system

Description: Photorefractive Intrastromal CXL (PiXL™) procedure (via Avedro’s Mosaic™ System) offers non-surgical refractive correction with Accelerated CXL alone, thus eliminating the risk of weakening the corneal structure and integrity. PiXL both strengthens the cornea and restores its biomechanical stability. Currently indicated for low myopia and postoperative cataract patients with uncorrected myopia.

14004789; Phase N/K; China; treatment group=30; Pending

studied. Expert: could allow topography guided CXL. http://avedro.com/medical-professionals/procedures/pixl/

99 Collagen cross-linking, corneal, rapid (30mW/cm2 for 4 minutes)

Corneal ectasia, progressive

Developer: Moorfields Eye Hospital (UK) Description: Continuous mode UVA with a UV-A power 30mW/cm2 for 4 minutes.

Phase N/A; 33 eyes

Expert: Alternative protocols for CXL need to be studied. Royal College of Ophthalmologists Annual Meeting Expert:

CXL, accelerated and contact lens assisted

100 Collagen cross-linking, corneal, contact lens assisted (ACACXL)

Keratoconus (with thin corneas)

Developer: Dr Agarwal's Group of Eye Hospitals and Eye Research Center (India) Description: Accelerated contact lens assisted collagen CXL of thin corneas (less than 400 μm after epithelial abrasion).

Phase N/A; 14 eyes

Expert: Alternative protocols for CXL need to be studied, especially in thin corneas. http://www.ofthalmologikokentro.gr/pdf/publications/publication_600_1.pdf

101 Collagen cross-linking, corneal with riboflavin (C3R) with pre-

Corneal ectasia (keratoconus, pellucid marginal degeneration or

Developer: Moorfield Eye Hospital Special Trustees (UK) Description: 1 week wearing specially-made contact lenses prior to CXL

ISRCTN29378493; Phase N/K; United Kingdom; n=20;

Expert: Alternative protocols for CXL need to be studied. Expert: Is this still an active study?

87

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

operative orthokeratology

post-excimer laser corneal ectasia) in tolerant/limited tolerance of contact lenses.

procedure in people with corneal ectasia (keratoconus, pellucid marginal degeneration or post-excimer laser corneal ectasia) who are intolerant or with limited tolerance of contact lenses for whom the only other options would be INTACS or corneal grafting.

completed 2008 http://isrctn.com/ISRCTN29378493

CXL, accelerated and in corneal pocket

102 Collagen cross-linking, corneal, accelerated, with corneal implant with Femtosecond Intrastromal Lenticule Implantation (FILI)

Keratoconus, mild to moderate, progressive

Developer: Nethradhama Eye Hospital (India) Description: Corneal tissue implant and collagen CXL. A stromal pocket is made with a femtolaser followed by insertion of cryopreserved corneal donor corneal tissue (obtained from patients undergoing ReLEx SMILE for myopia correction) along with accelerated cross linkage using 0.1% riboflavin dye injection in pocket and exposure to UV radiation at 30mW/cm2 for 3.3 minutes.

CTRI/2014/09/005012; Phase N/K; India; n=30; n=6 (6 eyes)

Expert: Alternative protocols for CXL need to be studied. Expert: adding tissue to cornea is treatment of choice in ectatic corneal diseases like keratoconus Expert: Not enough detail http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=10061

103 Collagen cross-linking, corneal, epi-on with crosslinking using a corneal pocket

Keratoconus, progressive or Pellucid Marginal Degeneration

Developer: University of Torornto (Canada) Definition: Epi on corneal crosslinking appears to have a faster recovery but a limited longterm effect in the treatment protocol used. Pocket crosslinking appeared to be more effective in the medium term.

Phase N/A; n=24

Expert: Alternative protocols for CXL need to be studied. Expert: Still epithelium on so difficult to see how this would work https://ascrs.confex.com/ascrs/15am/webprogram/Paper17326.html

88

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

104 Collagen cross-linking, corneal with Fullring simultaneously

Keratoconus Developer: Farabi Eye Hospital, Tehran University Of Medical Sciences (Iran) Description: A a femtosecond laser is used to create a pocket in the corneal stroma at a depth of 300 microns and a diameter of 9 mm at the centre of the cornea and a fullring is then inserted. After 5 minutes riboflavin is injected and followed by 10 minutes of UV irradiation.

IRCT2015030813567N9; Phase N/K; Iran; n=60

Expert: Alternative protocols for CXL need to be studied. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2015030813567N9

Donor cornea preparation

105 Donor corneas with narrow scleral rims

Corneal transplantation

Developer: Chang Gung Memorial Hospital, Department of Ophthalmology (Taiwan) Description: Donor corneas with narrow scleral rims are often disqualified for Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), mainly because of fluid leak and low pressure when they are mounted onto an artificial anterior chamber (AAC) for cutting. A doughnut-shaped cushion was made from a surgical glove, which enabled a tight lock of the cornea to the AAC, enabling the chamber pressure to be raised and the microkeratome cutting to be completed. This allows DSAEK procedures to be completed and

Taiwan; case study

Expert: More effective use of donor corneal tissue. http://dx.doi.org/10.1097/MD.0000000000001597

89

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

avoids unwanted switching from endothelial keratoplasty to penetrating keratoplasty.

106 Donor corneas, pre-conditioned, for Microthin DSAEK and Descemet's membrane keratoplasty

Corneal disease Developer: Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust - Cornea Unit (UK) Description: Corneas in the microthin group were preconditioned to achieve a target central thickness of 530μm before graft dissection with a 350μm microkeratome head. Preconditioning involved stromal dehydration under pachymetric control using sterile airflow for 15-second increments.

UK; n=13 (n=6 microthin)

Expert: This can be done using standard equipment available in theatres. http://journals.lww.com/corneajrnl/pages/articleviewer.aspx?year=2013&issue=07000&article=00041&type=abstract

107 Donor Deturgescence for Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty

Endothelial Keratoplasty

Developer: Frimley Park Hospital (UK) Description: To determine whether donor cornea deturgescence prior to microkeratome cut (cutting of the graft) in Descemet’s Stripping Automated Endothelial Keratoplasty surgery can provide ultra-thin donor endothelial grafts.

DUT-DSAEK Version 5, 15455; Phase N/A

Expert: Producing ultra-thin DSAEK is important but may be overcome with new endothelial transplant techniques. http://www.hra.nhs.uk/news/research-summaries/dut-dsaek-version-5/

Keratectomy

108 Descemet membrane removal (central Descemet membrane only)

Fuchs' Corneal Endothelial Dystrophy

Developer: Tokyo University Hospital-Corneal transplantation section (Japan) Description: Evaluate postoperative visual acuity and corneal opacity/oedema after central

JPRN-UMIN000016217; Phase N/K; Japan; n=4; Enrolling by invitation

Expert: Alternative method to assess corneal endothelial recovery. Expert: could provide an alternative to endothelial keratoplasty http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPR

90

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Descemet membrane removal In eyes with Fuchs corneal endothelial dystrophy with central corneal oedema and opacity.

N-UMIN000016217

109 Femtosecond laser-assisted lamellar keratectomy (FSLK)

Corneal opacities due to anterior corneal dystrophies

Developer: Medical University of Innsbruck - Department of Ophthalmology (Austria) Description: FSLK was performed to remove a central corneal free cap of 9.5mm diameter at a depth of 110 to 140 µm in patients with a clinical diagnosis of granular corneal dystrophy type 3 (Reis Buecklers corneal dystrophy, RBCD), Thiel-Behnke corneal dystrophy (TBCD), granular corneal dystrophy type 1 (GCD), classic lattice corneal dystrophy (LCD), and macular corneal dystrophy (MCD).

Phase N/A; n=6 (8 eyes)

Expert: Not novel. http://www.eucornea.org/barcelona-2015/poster-abstracts-barcelona-2015?sessiom=58

Keratectomy, in combination with CXL

110 Collagen cross-linking, corneal in combination with wavefront-guided photorefractive keratectomy (using iDesign® Advanced WaveScan

Keratoconus Developer: Ottawa Hospital Research Institute; Abbott Medical Optics Description: Corneal collagen crosslinking combined with photorefractive keratectomy has been explored to partially correct the refractive error in keratoconic patients, whilst simultaneously stabilizing the corneal changes. Recently, the iDesign® Advanced

NCT02613780; Phase 3; n=24

Expert: Additional methods for visual rehabilitation in keratoconus are needed. Expert: limited to centres with this technology. https://ClinicalTrials.gov/show/NCT02613780

91

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Studio (iDesign system; Abbot Medical Optics; Santa Ana, CA), the most advanced high-resolution aberrometer)

WaveScan Studio (iDesign system; Abbot Medical Optics; Santa Ana, CA) has been launched as the most advanced high-resolution aberrometer. It is capable of mapping highly refractively aberrated corneas for wavefront-guided laser procedures.

111 Collagen cross-linking, corneal, epi-off with phototherapeutic keratectomy (PTK) or photorefractive keratectomy (PRK)

Keratoconus, mild or moderate or post-refractive corneal ectasia

Developer: Boulder Eyes Clinic (USA) Description: Epithelium-off CXL in combination with either PTK (n=4) or PRK (n=5). Riboflavin was administered every 30 seconds for 15 minutes followed by UV irradiation using the UV-360 Crosslink device (New Vision, Inc.) at 25 mW for 6, 30 second sessions.

Phase N/A; 9 eyes

Expert: Additional methods for visual rehabilitation in keratoconus are needed. https://ascrs.confex.com/ascrs/15am/webprogram/Paper13865.html

112 Collagen cross-linking, corneal, post customised photorefractive keratectomy (PRK)

Keratoconus, progressive

Developer: Azienda Ospedaliera Policlinico di Bari - University hospital consortium Bari - Department of Ophthalmology (Italy) Description: Customised topographic photorefractive keratectomy (PRK) followed by corneal CXL in a single procedure for progressive keratoconus.

ISRCTN57262986; Phase N/K; Italy; n=20; Completed

Expert: Additional methods for visual rehabilitation in keratoconus are needed. http://isrctn.com/ISRCTN57262986

113 Emirates Protocol: using a high-tech-laser trans

Keratoconus Developer: New Vision Eye Centre (Dubai) Description: This procedure is done without corneal debridement with

Phase N/A; 40 eyes

Expert: Additional methods for visual rehabilitation in keratoconus are needed. Expert: heavily technology dependent. https://ascrs.confex.com/ascrs/15am/webprogram/Pap

92

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

epithelial photorefractive keratectomy (PRK) combined with A-CXL

alcohol, and the laser is guided by corneal high-order aberration (HOA) management system. This is immediately followed by accelerated CXL. The Emirates protocol uses high-tech-laser, aspheric transepithelial topographic aberrometric-guided PRK laser-guided by corneal high-order aberration (HOA) management that has 2 modules (refractive and pyramid) to select the clinical significant HOA and the best refractive error. The HOA Management incorporates HOA and refractive error algorithmically taking into consideration: optical zone must cover the outer border of the cone, and resulted thinnest point is not less than 300µm postop.

er10451.html

114 Intrastromal corneal ring segment implantation via transepithelial Phototherapeutic keratectomy (PTK), with accelerated corneal collagen

Keratoconus Developer: Toronto Western Hospital - Department of Ophthalmology and Vision Sciences (Canada) Description: Combined same day transepithelial phototherapeutic keratectomy (t-PTK) with Intacs-SK0.5mm insertion (new intrastromal corneal ring segments with larger cross sectional diameter and smaller inner optical zone) and accelerated

Phase N/A; 19 eyes, n=12 patients

Expert: Additional methods for visual rehabilitation in keratoconus are needed. https://ascrs.confex.com/ascrs/15am/webprogram/Paper13468.html

93

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

cross-linking corneal collagen crosslinking using increased optical intensity to shorten treatment time.

Keratoplasty

115 Collagen cross-linking, corneal, epi-on with conductive keratoplasty (CK)

Keratoconus and Corneal Ectasia

Developer: CXL-USA (US corneal specialists formed a non-commercial, physician-sponsored research group) (USA) Description: non-invasive method of CK combined with proprietary epi-on (transepithelial) CXL procedure. CK was performed using intraoperative keratometry, a new spot nomogram; CXL was performed within 36 hours. CK spots were applied either superiorly, apically, or both.

NCT01024322; Phase N/A; ; n=113 (155 eyes)

Expert: Novel method for developing an alternative CXL protocol. Patient focus groups: Conductive keratoplasty would revolutionise life for people with keratoconus as it would mean no lenses and no surgery. https://ascrs.confex.com/ascrs/15am/webprogram/Paper14023.htm l

116 Conductive keratoplasty

Keratoconus and keratoectasia

Developer: Kyoto Prefectural University of Medicine (Japan) Description: Conductive Keratoplasty (CK) is a noninvasive procedure which utilizes radiofrequency energy. It is currently indicated for the correction of presbyopia and low hyperopia with or without astigmatism and residual refractive error after laser in-situ keratomileusis (LASIK) or cataract surgery.

JPRN-UMIN000002484, Phase N/K, Japan, n=40, status N/K; JPRN-UMIN000000886, Phase N/K, Japan, n=30, Not yet recruiting

Expert: Not wholly novel but better methods for correcting presbyopia needed. Patient focus groups: Conductive keratoplasty would revolutionise life for people with keratoconus as it would mean no lenses and no surgery. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000002484

94

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Laser masking agent

Patient focus groups: The poor reputation of corrective laser eye surgery affected the perception of participants about options involving laser.

117 Gentian violet and cyanoacrylate glue as double masking agents to defocus the femtosecond laser raster pass during keratoplasty

Corneal ectasia consistent with recurrent keratoconus

Developer: Warfighter Refractive Surgery Center, Wilford Hall Ambulatory Surgical Center andEmory University School of Medicine (USA) Description: Masking agents are applied to thin areas of cornea to prevent perforation of the cornea during femtosecond laser dissection during anterior lamellar keratoplasty.

Phase N/A; case study

Expert: Novel use of agents. Expert: case study http://journals.lww.com/corneajrnl/Abstract/2014/03000/Novel_Approach_for_the_Treatment_of_Corneal.19.aspx

Magnetophotophoresis

118 Magneto-photophoresis

Corneal oedema, postoperative

Developer: Victor Egorov (Russian Federation) Description: Application of a magneto-photophoresis, photophoresis, a form of apheresis and photodynamic therapy in which tissue is treated with a photosensitizing agent and subsequently irradiated with specified wavelengths of light to achieve an effect but under the influence of a magnetic field.

Phase N/A; no info

Expert: Developing technology. Expert: difficult to assess what they are trying to achieve. European Society of Ophthalmology Congress, 2015, Vienna, Austria

Oxygen to aid recovery

119 Hyperbaric Corneal burns, Developer: Eye Clinics of Gülhane Phase N/A; Expert: Novel protocol.

95

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

oxygen and mitomycin-C assisted limbal minitransplantation

severe alkaline, associated with total limbal insufficiency

Military Medical Academy& Hospitals - Cornea & Refractive Surgery Dept. (Turkey) Description: HBOT (Hyperbaric oxygen treatment) and MMC assisted limbal minitransplantation. Neovascular membranes and symblepharons were removed, corneal limbus exposed to 0.01mg/ml MMC for 1 min, and 4x3 mm size limbal autograft from the fellow eye or allografted. Patients then underwent HBOT therapy ( 2.4 ATA, %100 oxygen saturation, for 90 minutes).

n=24 (27 eyes) Expert: Requires hyperbaric oxygen chamber. Limited use. http://www.escrs.org/istanbul2015/programme/posters-details.asp?id=22684

120 Oxygen therapy, transcorneal and systemic

Corneal oedema following cataract surgery

Developer: Ahvaz Jundishapur University of Medical Sciences (Iran) Description: Transcorneal oxygen therapy as an adjunct to conventional therapy for severe corneal oedema may preserve more endothelial cells and decrease corneal oedema faster. Corneal oedema with a rise in corneal thickness increases the distance for oxygen to reach the endothelium and thereby theoretically keeps the remaining endothelial cells under a relatively hypoxic state, supplemental oxygen might improve endothelial pump function and restore corneal clarity. Routine treatment and oxygen

IRCT2012113011619N1; Phase N/K; Iran; n=45; completed

Expert: The use of oxygen therapy is interesting. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2012113011619N1

96

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

100% by an eye shield with flow rate of 5 L/minute for 1 hour twice daily, for3 weeks or routine treatment and oxygen 100% by a facial mask with flow rate of 10 L/minute for 1 hour twice daily for 3 weeks.

Partial thickness corneal transplant

121 Corneal stromal transplantation

Corneal stromal thinning

Developer: Minami aoyama eye clinic - Ophthalmology (Japan) Description: Corneal stromal transplantation (donor stroma prepared by femto-second laser) in cases with corneal stromal thinning including keratoconus

JPRN-UMIN000020256;Phase N/K; Japan; n=10; Not yet recruiting

Expert: Not novel but needs further study. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000020256

122 Descemet membrane endothelial keratoplasty (DMEK)

Keratopathy, Bullous

Developer: Osaka University Graduate School of Medicine - Department of Ophthalmology (Japan) Description: DMEK is a partial-thickness cornea transplant procedure that involves selective removal of the patient's Descemet membrane and endothelium, followed by transplantation of donor corneal endothelium and Descemet membrane without additional stromal tissue from the donor. The graft tissue is merely 10-15 microns thick.

JPRN-UMIN000014242; Phase N/K; Japan; n=10; Open public recruiting

Expert: Not novel. Expert: 3rd generation of endothelial keratoplasty, innovative in evolution, slowly adapted by surgeons due to long learning curve http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000014242

123 Endothelial keratoplasty

Bullous keratopathy,

Developer: Singapore National Eye Centre (Singapore)

Phase N/A; ; 113 eyes (n=32

Expert: Already in practise. Expert: results already published

97

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

after failed penetrating keratoplasty

pseudophakic, with failed penetrating keratoplasty

Description: To analyze graft survival of endothelial keratoplasty under a previous failed penetrating keratoplasty.

EK under failed PK; n=81 repeat PK)

http://dx.doi.org/10.1016/j.ajo.2014.08.024

124 Lamellar excision and donor corneal stromal lenticule lamellar placement to prevent recurrence

Recurrent intrastromal epithelial inclusion cyst in a corneal graft

Developer: All India Institute of Medical Sciences - Centre for Ophthalmic Sciences (India) Description: Intracorneal epithelial corneal cysts managed with lamellar excision and donor corneal stromal lenticule lamellar placement to prevent recurrence.

Phase N/A; case study

Expert: Rare complication. http://dx.doi.org/10.1136/bcr-2014-209273

125 lamellar keratoplasty with pleat technique

Keratoglobus Developer: Gartnavel General Hospital - Tennent Institute of Ophthalmology (UK) Description: A modified anterior lamellar keratoplasty with pleat technique to achieve satisfactory visual rehabilitation in extreme keratoglobus. This pleat technique addresses the fundamental structural problem of a superiorly and vertically displaced limbus and the corresponding abnormal corneal white-to-white diameter in keratoglobus.

Phase N/A; case study

Expert: Rare disease. Expert: case report http://dx.doi.org/10.1097/ICO.0000000000000315

126 pre-Descemet's endothelial keratoplasty

Corneal endothelial disease

Developer: Dr. Agarwal's Eye Hospital and Eye Research Centre (India) and University of Nottingham -Academic

Phase N/A; n=5, 5 eyes

Expert: Alternative method for procuring DMEK tissue. Expert: 3rd generation of endothelial keratoplasty, innovative in evolution, slowly adapted by surgeons due

98

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

(PDEK) Ophthalmology (UK) Description: A new surgical technique for endothelial keratoplasty in which the Pre-Descemet's layer (Dua's layer) with Descemet's membrane and endothelium is transplanted subsequent to the removal of the recipient's Descemet's membrane.

to long learning curve Expert: published http://dx.doi.org/10.1136/bjophthalmol-2013-304639

Partial thickness corneal transplant, in combination with prosthesis

127 Femtosecond laser-assisted epidescemetic keratoprosthesis

Corneal disease Developer: Universidad Miguel Hernández - Division of Ophthalmology (Spain) Description: a new model of epidescemetic keratoprosthesis with combined corneal graft associated with KeraKlear implantation assisted by femtosecond laser.

Phase N/A; case study; 15 eyes (4 epidescemetical; 11 intralamellar)

Expert: Rare use. Expert: Case report http://dx.doi.org/10.5301/ejo.5000435

Partial thickness corneal transplant using microkeratome pocket maker

128 Ultrafine Descemet stripping pocketmaker endothelial keratoplasty (DSPEK) automated using microkeratome

Keratopathy, bullous, stage I-III, secondary

Developer: Ufa Eye Research Institute (Russia) Description: Automated DSPEK was performed using the microkeratome Pocket Maker to implant ultra-thin transplants with a thickness of 70-110 microns. Microkeratome pocket maker was originally indicated for intracornel ring implant.

Phase N/A; n=35 (37 eyes)

Expert: Need for better methods in endothelial surgery. http://www.eucornea.org/london-2014/london-2014-posters?sessiom=33

99

# Technology Indication Description *Stage of development

Further information: expert comments, source/web link

Pocket Maker

Simple excision and conjunctiva covering Back to results contents

129 Simple excision, corneal tattooing, and sutureless limboconjunctival autograft;

Corneal limbal dermoids (grade 1), paediatric

Developer: Jeju National University College of Medicine and Seonam University College of Medicine - Department of Ophthalmology (Korea); Takumi, H. ; Matsumoto, T. ; Katayama, Y. et al (case study) (Japan) Description: Combined surgery of simple excision, corneal tattooing, and a sutureless limboconjunctival autograft in pediatric patients with grade 1 limbal dermoids.

Phase N/A; n=4, 4 eyes; case study

Expert: Rare disease. Expert: limited case report. http://dx.doi.org/10.1097/ICO.0000000000000440

Stain to highlight tissue during surgery

130 VisionBlue stain for DMEK surgery

Keratopathy, bullous

Developer: Keio University School of Medicine -Department of ophthalmology (Japan) Description: Endothelial sheet was stained by Visoin Blue for 1min during DMEK surgery. Vision Blue is currently indicated for cataract surgery.

JPRN-UMIN000020253; Phase N/K; Japan; n=10; not yet recruiting

Expert: The need for dyes in endothelial surgery requires further study. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000020253

100

APPENDIX 6: COMMENTS FROM FIGHT FOR SIGHT

The final conclusions from Fight for Sight were as follows: 1. The stage of a patient’s sight loss ‘journey’ must be taken into account in pre and post treatment

care.

2. Long-term patients may have developed a protective scepticism over time when discussing new treatments/procedures and can ask pertinent questions, whereas inexperienced patients must necessarily take more on trust. The scientific and medical professions should be aware of this and compensate for it when offering up treatments or procedures to patients. This could be addressed with clearer and more accessible information along the lines of prescription medicine patient information leaflets, to be made available for every specific treatment or procedure offered.

3. It would be useful to know whether local or general anaesthetic is required for the treatments. There was a widespread feeling that a local anaesthetic leaves the patient in more control and this improves confidence in the treatment.

4. Have patients been involved in the research other than as trial participants? At what stages of the process? Patient involvement is an indicator of acceptability

5. People who had not totally lost their sight were keen to know risks and complications so they could weigh up whether the benefits were worth it. They said that the sight they have left becomes even more precious so they don’t want to do anything which might cause further damage.

6. It was also unclear what effects a treatment would have on other conditions the patient lives

with, in particular co-morbidities affecting the eye, e.g. congenital glaucoma and the effect of a rapid reduction of intraocular pressure due to treatment for a corneal disorder.

Barriers: 1. There is nervousness about the introduction of any new technique if it isn’t delivered via a health

professional the patient already has confidence in. Eyes are very sensitive and sight precious. Many patients are unwilling to allow an unknown eye health professional to complete a procedure or even a known and trusted professional who has not got the experience in the new treatment. This could prove a barrier to implementation of any innovation. The onus is on the eye health professional to instil confidence in their skill and that the treatment is appropriate and effective not just being tried because it is new and therefore exciting. This can be summed up by the comment ‘it’s not the new drugs I find worrying but the healthcare system around them.’

2. There was a feeling that primary care practitioners – particularly GPs – require more

understanding of eye health and prevention as well as awareness of potential new treatments. 3. Attendees shared a frustration that healthcare professionals usually assumed they had someone

to look after them on leaving hospital. This can put the success of the treatment at risk if they are left to self-administer.

4. Anything which was seen as an invasive treatment was viewed as a last resort option without any

accompanying risk analysis.

101

Communicating: 1. It is essential that eye health professionals provide information including effectiveness, potential

side effects or damage and convenience. It is impossible to make an informed decision about a treatment without a full explanation. If a treatment was to be extremely effective then patients would choose it even if it was inconvenient. The patients need to feel empowered to assess risk and be in control of their treatment and treatment options.

2. There is a danger of poor communication leading the patient to think something is a ‘miracle

cure’ especially if they are not given the failure rate and full cognisance of risk. Procedures described by the media as ‘breakthroughs’ don’t help.

102

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Functional Biomaterials 2015;6(2):277-298. 12 The College of Optometrists. Guidance and Professional Standards. Accessed 15th December 2015.

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23 National Institute for Health and Care Excellence. Implantation of a corneal graft–keratoprosthesis for severe corneal opacity in wet blinking eyes. Interventional procedure guidance IPG534. London: NICE; November 2015.

24 National Institute for Health and Care Excellence. Insertion of hydrogel keratoprosthesis. Interventional procedure guidance IPG69. London: NICE; June 2004.

25 Dua HS, Saini JS, Azuara-Blanco A, et al. Limbal stem cell deficiency: concept, aetiology, clinical presentation, diagnosis and management. Indian Journal of Ophthalmology 2000; 48:83–92.