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New and emerging technologies in glaucoma

Horizon Scanning Centre

March 2013

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This report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s)

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

The NIHR Horizon Scanning Centre, University of Birmingham, United Kingdom

nihrhsc@contacts.bham.ac.uk www.hsc.nhir.ac.uk

Copyright © University of Birmingham 2013

mailto:nihrhsc@contacts.bham.ac.ukhttp://www.hsc.nhir.ac.uk/

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CONTENTS

Executive summary .................................................................................................. 4

Acknowledgments.................................................................................................... 5

1. Introduction .......................................................................................................... 6 1.1 Clinical need and burden of disease ................................................................. 6

1.2 Aims & objectives .............................................................................................. 7

2. Methods ................................................................................................................ 8

3. Diagnosis and monitoring in glaucoma ............................................................ 9 3.1 New approaches ............................................................................................... 9

3.2 New technologies identified ............................................................................ 10

3.2.1. Measuring IOP ......................................................................................... 10

3.2.2. Visual field testing .................................................................................... 13

3.2.3. Optic nerve and retinal nerve fiber layer assessment .............................. 13

4. Treatment of glaucoma ...................................................................................... 15 4.1 New approaches ............................................................................................. 15

4.2 New technologies identified ............................................................................ 16

4.2.1. Pharmaceuticals ...................................................................................... 17

4.2.2. Laser treatment........................................................................................ 19

4.2.3. Ultrasound .............................................................................................. 21

4.2.4 Surgery .................................................................................................... 22

5. References .......................................................................................................... 27

Appendices ............................................................................................................. 29

Appendix 1 Detailed methods ............................................................................... 29

Appendix 2 Excluded technologies ....................................................................... 31

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EXECUTIVE SUMMARY

The aim of this review was to identify new and emerging technologies including drugs, medical devices and surgical procedures for the diagnosis, monitoring and treatment of glaucoma. Glaucoma presents a significant and increasing burden upon the UK National Health Service with around one in ten people over the age of 75 being affected.

Searching of bibliographical databases, clinical trial registries, technology databases and other online sources was combined with consultation with clinical experts to identify relevant new technologies. Commercial developers were then contacted to gather further information and to ascertain licensing and availability plans.

Twenty six new and emerging technologies were identified; four for diagnosis/monitoring and twenty two for the treatment of glaucoma. Clinical experts were asked about the potential future impact of these devices upon the care pathway and patient outcomes.

A number of the technologies identified were of particular clinical interest.

Experts say that a device that accurately monitors 24 hour intra-ocular pressure (IOP) would revolutionise the management of glaucoma. We identified devices that are taking steps in that direction including one early device which is intended to be implantable so allowing pressure measurements from the inside of the eye for the first time. Self-measurement of IOP by the patient at home is also likely to become a possibility which should improve patient outcomes and save NHS resources.

In treatment there is a well recognised and significant problem of compliance with daily long-term eye drop therapy especially when they cause irritation to the eyes. Sustained release versions of existing drugs, as well as preservative free versions are in development which experts say may become a major growth area with important clinical consequences. They worry that the probable extra costs of these newer versions may act as a barrier to their wide usage in the NHS.

In surgical treatment various new techniques and devices for ‘minimally invasive’ glaucoma surgery are being developed or are starting to be used in specialist centres. These are of great interest to some experts who say that they may, in time, lead to earlier surgical intervention in the pathway of care for a person with glaucoma, so reducing the need for lifelong eye drops – a major change in management. Another interesting mode of treatment in development for glaucoma is ultrasound. If shown to be effective and possessing a good safety profile, experts say that treatment with devices using ultrasound therapeutically might become popular in an outpatient setting and at an early stage of the disease.

Experts comment that this is a time of great innovation in the diagnosis and management of glaucoma and careful assessment and appropriate adoption by the

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NHS of new technologies needs to be undertaken in order to realise the benefits that this innovation may bring to patients and healthcare resources.

ACKNOWLEDGMENTS Internal review team Zaheda Teladia, Horizon Analyst, Dr Kristina Routh, Clinical Senior Lecturer and Medical Advisor NIHR Horizon Scanning Centre Expert advisors Professor Pete Shah, Professor of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust.

Mr Imran Masood, Consultant Ophthalmic Surgeon, Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Foundation Trust.

Professor Stephen A Vernon, Professor of Ophthalmology, University Hospital Nottingham.

Mr Richard Wormald, Consultant Ophthalmologist, Moorfields Eye Hospital, London.

Statement of conflicts of interest (COI).

Professor Pete Shah states no COI with respect to this report but notes he has been involved in educational events with Allergan UK during the period of work on this document.

Mr Imran Masood states that “I am trained to use the trabectome, Istent and Hydrus. I am currently using the Istent in regular clinical practice and am conducting a trial of the Hydrus device. When this piece of work was undertaken there was no COI”. He also notes he has been involved in educational events with Allergan.

Professor Stephen A Vernon and Mr Richard Wormald state no COI.

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1. INTRODUCTION

The diagnosis, monitoring and treatment of glaucoma appear to have been active areas of technological development in recent years. These advances may have a significant impact on the way glaucoma is managed in the future.

1.1 CLINICAL NEED AND BURDEN OF DISEASE

Glaucoma is the name given to a group of medical conditions of the eye where there is progressive damage to the optic nerve. Normally, the ciliary body secretes aqueous humour into the eye and this fluid flows out of the eye via the trabecular meshwork. Changes to this process can cause intraocular pressure (IOP) within the eye to increase. An increase in this pressure is associated with a greater risk of developing glaucoma and disease progression, although glaucoma may occur with normal intraocular pressure1,2,3. Most commonly, glaucoma leads to a gradual loss of vision and may cause blindness. The condition often develops slowly, with the outer peripheral field of vision being lost first. For this reason people with glaucoma often do not realise that their sight is being damaged until the disease is advanced. Damage to vision cannot be repaired and once diagnosed, lifelong monitoring is needed1,2.

There are four main types of glaucoma:

• Primary open-angle glaucoma (figure 2) – a chronic disease, which may be hereditary. In chronic open angle glaucoma (COAG), the trabecular meshwork becomes partially blocked preventing the aqueous humour draining properly and therefore raising intraocular pressure.

• Acute angle-closure glaucoma (figure 2) – a rare disease which is thought to be under-diagnosed5. It is caused by a narrowing angle between the iris and sclera of the eye, which blocks the trabecular meshwork. The narrowing can happen very quickly and causes a sudden and painful build-up of pressure in the eye.

• Secondary glaucoma – open angle or closed angle glaucoma caused by another condition e.g. diabetes.

• Developmental glaucoma - developmental glaucoma is rare, but it can be serious. It is usually present at birth, or develops shortly after birth. Developmental glaucoma is caused by an abnormality of the eyeball.

Figure 1: Production and flow of aqueous humour in the eye. © 2013 British Journal of Anaesthesia

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By far the most common type of glaucoma in the UK is COAG2 and over 480,000 people in England are estimated to be affected although only 158,000 of these are diagnosed3. Amongst white Europeans around 1 in 50 people aged over 40 years and 1 in 10 aged over 75 years have COAG3. The prevalence may be higher for people of black African or black Caribbean descent and for those who have a family history of glaucoma3. The National Institute for Health and Care Excellence (NICE) estimates that over 111,000 patients with COAG in England are likely to need management in hospital each year4. It also estimates that each year 11,735 people in England are likely to progress from moderate to severe glaucoma and be at risk of losing their sight despite treatment4. Although numbers may vary according to local factors, this is equivalent to over 22 patients per 100,000 population. Other types of glaucoma are less common in the UK.

1.2 AIM & OBJECTIVE

The aim of this review was to identify new and emerging technologies including drugs, medical devices and surgical procedures for the diagnosis, monitoring and treatment of glaucoma.

The purpose of this work is to provide information to healthcare policy makers, commissioners, clinicians and patient groups about new technologies that may be of relevance in the future of glaucoma management. This report, which has been informed by consultation with clinical experts, is not intended to provide a complete overview on all new and emerging technologies for glaucoma but to report on those most likely to have an impact on the care pathway and healthcare resources.

Figure 2: Flow of aqueous humour in open angle and closed angle glaucoma

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2. METHODS

New and emerging technologies for the diagnosis, monitoring and treatment of glaucoma were sought by searching the outputs and database of the NIHR HSC6 and Euroscan7 together with a targeted, but limited search for published papers, reviews and on-going clinical trials. Searching was augmented with a general internet search for emerging technologies using the Google search engine. Online sources used included:

• Technology databases and reports; HTA programme and Medica • Medline, Embase and Cochrane research databases • Clinical trial registries • Clinica for intelligence on medical technologies for glaucoma • Conference reports and abstracts from major ophthalmology journals suggested

by experts

Experts from the field of glaucoma were recruited and asked to provide information on new and emerging glaucoma technologies known to them. The criteria used for inclusion of technologies were: • Pharmaceuticals that are within 24 months of licensing • Medical technologies that are: o emerging’ - expected to be CE marked (where appropriate) or launched within

the UK in the next 24 months o ‘new’ - CE marked (where appropriate) and has usually only been available for

clinical use for ≤12 months and is generally in the launch or early post-marketing stages.

o ‘new and poorly adopted’ – medical technologies that are within 2 years of launch and poorly (

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3. DIAGNOSIS AND MONITORING IN GLAUCOMA

Early detection and diagnosis of glaucoma is important to prevent or avoid further visual loss. An ophthalmologist may diagnose glaucoma during a routine eye examination using techniques such as;

• Intra-ocular pressure (IOP) measurement using tonometry • Central corneal thickness • Gonioscopy to determine whether the glaucoma is open or closed angle • Visual field measurement • Optic nerve assessment

A range of diagnostic tests are required to confirm diagnosis as there are two clinical features that complicate the diagnosis of glaucoma. The first is ocular hypertension (OHT), where IOP lies outside the normal range without any clinically detectable signs of glaucomatous optic neuropathy. The second is when individuals develop glaucomatous optic neuropathy in the absence of raised IOP.

NICE published guidance on the diagnosis and management of chronic open angle glaucoma and ocular hypertension in April 2009.

3.1 NEW APPROACHES

Earlier diagnosis

Early detection of glaucoma during a standard eye test would help guide earlier decisions about patient referrals to specialist care. Introducing imaging as a regular part of glaucoma practice is of interest and well established imaging devices such as optical coherence tomography are being incrementally developed into smaller, low cost, portable versions more suited to a primary care setting.

Continuous IOP monitoring

Monitoring of treatment and identification of progression of disease in glaucoma would be greatly improved by the ability to measure the IOP more frequently and without the need for a hospital visit. New devices for 24 hour home monitoring of IOP are being developed. Daily self-monitoring IOP devices can reduce the number of clinic visits and the proactive approach of the clinician may help to increase patient compliance to treatment. These devices have the potential to change the management of glaucoma patients with an emphasis on remote patient management.

http://www.nice.org.uk/nicemedia/live/12145/43839/43839.pdf

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3.2 NEW TECHNOLOGIES IDENTIFIED

We identified four new technologies for the diagnosis and/or monitoring of glaucoma.

3.2.1 MEASURING IOP

Sensimed Triggerfish®

Sensimed Triggerfish®, developed by Sensimed AG, (distributed by Kestrel Ophthalmics in the UK) is the first commercially available, non-invasive device designed to provide 24-hour monitoring of intraocular pressure fluctuations in adults with chronic glaucoma. The device consists of a disposable soft silicone contact lens containing a sensor, a flexible disposable self-adhesive antenna placed around the eye and a pocket-sized recorder (attached by a wire to the antenna and worn around the patient’s neck). The recorder sends the collected information to the doctor’s computer via Bluetooth at the next consultation. The company estimates that patients may be monitored for 24 hours between three-monthly and yearly, depending on the stability of their intraocular pressure.

The Sensimed Triggerfish® was CE marked in May 2009 and was launched in the UK in the first quarter of 2012. It is also commercially available in Canada and Australia but not yet FDA approved in the United States. The initial capital cost of the device is approximately £6,000. In addition to this, the cost per patient use (for the disposable items) is £550.

The NIHR HSC has produced a detailed briefing for the Sensimed Triggerfish®.

Expert opinion: A device that can accurately measure the true values of IOP over 24 hours would revolutionise glaucoma management. Sensimed Triggerfish® provides relative IOP measurements rather than absolute measurements of IOP and so it’s potential for use in glaucoma monitoring is unclear. It may be difficult to tolerate wearing a contact lens for 24 hours for a significant proportion of the at risk population.

http://www.sensimed.ch/http://www.kestrelophthalmics.com/sensimed-triggerfishhttp://www.kestrelophthalmics.com/sensimed-triggerfishhttp://www.hsc.nihr.ac.uk/topics/sensimed-triggerfish-for-24-hour-monitoring-of-cha/

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Icare ONE tonometer

The Icare ONE tonometer has been developed by Icare Finland Oy (distributed by Mainline Ltd) for the screening and self-monitoring of IOP in patients with glaucoma. It is based on a rebound measuring principle, in which a magnetised probe is propelled against the cornea using a solenoid. The solenoid detects the motion and impact of the probe when it touches the cornea and bounces back. The moving magnet in the probe induces voltage in the solenoid, and the motion parameters are recorded.

The Icare ONE tonometer can be used without the need for topical anaesthetic and patients can self-monitor IOP daily which may reduce the number of hospital visits for a patient. Furthermore the ability to measure IOP outside normal clinic hours may be able to detect peaks and fluctuations in IOP which would otherwise not be measured. This may be valuable for patients who seem to have normal IOP in clinic hours but whose glaucoma continues to worsen. Results can also be saved immediately at the time of measuring.

The reliability of the Icare ONE tonometer depends on the patient’s ability to self-administer the test correctly. There have been several trials looking at whether the Icare ONE tonometer can provide accurate measurement of IOP compared to an experienced user and other measurement devices such as Goldmann tonometry.

The Icare ONE tonometer was CE marked in December 2009. It is currently in pre-commercial stage in the UK and is only available as part of a clinical trial at the Institute of Ophthalmology, London, UK. The Icare ONE tonometer is licensed and launched in Canada and Australia but not yet FDA approved in the United States. The cost of the device is £896 + VAT. In addition to this, the cost per patient use per day (1 probe per day) would be £1.14.

Expert opinion: The main innovation of the Icare one tonometer is that it allows a patient to take repeated measurements of their IOP in their own home, perhaps using devices lent out by the hospital clinic. This device has the potential to save NHS resources by reducing the number and length of inpatient stays associated with the need for multiple IOP measurements in some patients. It is considered to be a minimally invasive and accurate and may be particularly useful in children.

http://www.icaretonometer.com/

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ARGOS IO

ARGOS IO is an implantable IOP sensor being developed by Implandata Opthalmic Products GmbH, for patients with glaucoma at any stage of disease. The system consists of an implantable silicone microsensor eye implant, with membranes for pressure sensing. An external hand held device transfers energy to the micro sensor telemetrically which powers the chip to take pressure readings and also record measurements. It is anticipated that the device will be robust and durable enough to accurately sense IOP for 10-15 years. ARGOS IO is said to be suitable for patients who are stable and require one or two measurements a day. If continuous measurement of IOP is required, an external antenna is integrated into a night mask or the frame of spectacles where it allows patients to check IOP pressures continuously and share data with their doctor via telemedicine infrastructure.

ARGOS IO is intended to be used in addition to tonometry for the diagnosis and monitoring of all patients with glaucoma, but in particular patients who have refractory disease. Since the procedure is invasive it is intended to be used in patients who have cataracts and glaucoma so that the device may be implanted at the same time as cataract surgery. The continuous measurement of IOP may be useful in patients whose IOP fluctuates and where episodic pressure measurements in the clinic may not accurately be able to manage the patient’s glaucoma. Furthermore integration into telemedicine infrastructure will allow remote patient management.

ARGOS IO is not yet CE marked.

Expert opinion continued: A potential barrier to the use of the Icare one tonometer is cost as tonometry devices are already available for clinical use in hospitals. It is also noted that the patient needs to be motivated and able to self-monitor their IOP and report readings to their ophthalmologist.

http://www.implandata.com/http://www.implandata.com/http://www.implandata.com/images/24h.jpg

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3.2.2 VISUAL FIELD TEST

Moorfields detection test

The Moorfields Motion Displacement Test (MDT) is a new test for the detection of glaucoma which is currently in development at Moorfields Eye Hospital and the Institute of Ophthalmology, UCL , in collaboration with City University, London. The Moorfields MDT is designed to run on a standard computer and is a test of the field of vision.

The test is based upon the finding that the ability for a person to detect the motion of a moving line in their visual field is reduced in those with glaucoma. The test is designed to be delivered using a simple computer and without the need for a highly trained medical or technical operator. The patient is asked to look at the computer screen and to indicate by clicking the computer mouse when they see a line move. The threshold (i.e. the distance moved) at which motion is detected is greater in patients with glaucoma than in those with normal eyes. It is said to be a robust and portable test which is simple to operate and which is suitable for use in a wide range of healthcare scenarios including primary care in the UK. MDT is not yet CE marked.

3.2.3 OPTIC NERVE AND RETINAL NERVE FIBRE LAYER ASSESSMENT

Optical coherence tomography (OCT)

Optical coherence tomography (OCT) is currently used as an adjunct to clinical assessment for the diagnosis of glaucoma in a hospital setting. OCT technology has the ability to accurately confirm or dismiss the diagnosis of glaucoma at an earlier

Expert opinion: Moorfields MDT has been developed over the last twenty years. Modern computerisation should improve the likelihood of this becoming a routine test used for glaucoma detection. It has various advantages over traditional perimetric tests including being less affected by cataract and refractive error.

Expert opinion: The major innovation of ARGOS IO is that it is implantable and therefore allows IOP to be measured directly from within the eyeball for the first time. Others methods of IOP measurement rely on external readings. In addition the ability to provide continuous measurement of IOP may improve patient management by providing better information on which to base treatment. Implantation at the same time as cataract surgery will help to minimise the extra risk inherent in a surgical procedure for an implantable device. This device might prove of benefit in all glaucoma patients and in particular for those with refractory glaucoma.

http://www.moorfieldsmdt.co.uk/http://www.moorfieldsmdt.co.uk/

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stage of disease. This promotes earlier intervention. It is not currently used as a stand-alone diagnostic test. Over the years the scanning speed and resolution have vastly improved.

A new multiple reference OCT (MRO-OCT) which is a small, low cost, flexible variant of time-domain OCT is in development by Optovue. It is anticipated that the MRO-OCT could be used by primary care practitioners for routine screening and monitoring of high risk patients to guide decisions about referrals to specialist care. By making diagnostic tests like the OCT more accessible in the primary care setting there is potential for improved early detection of glaucoma.

Expert opinion: OCT scanning is already an accepted test in hospital eye departments and community optometrists are purchasing these instruments to use in their practices. It is not new technology but evolving technology that has had a quantum leap in efficiency over the last few years. OCT is likely to increase in importance over the next few years as better databases become available.

http://www.optovue.com/

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4. TREATMENT OF GLAUCOMA

Glaucoma cannot be cured but treatment may help delay disease progression. Most treatments for glaucoma aim to reduce IOP levels. This can be achieved by either reducing the production of aqueous fluid or by increasing aqueous outflow. In clinical practice the following treatments may be used;

• Eye drops – prostaglandin analogues (increase outflow of aqueous fluid), beta-blockers (reduce production of aqueous fluid) and carbonic anhydrase inhibitors (reduce production of aqueous fluid).

• Laser trabeculoplasty – a laser burns tiny holes in the drainage area to increase aqueous outflow. Laser surgery is not a cure and patients with glaucoma still need to continue taking daily eye drops. An alternative to laser trabeculoplasty is cyclodiode laser treatment. This involves destroying some of the tissue in the eye that produces aqueous humour. There are several different types of laser and their use depends on the type of glaucoma and how severe it is.

• Surgery – Patients with severe and uncontrolled glaucoma are considered for filtration surgery with trabeculectomy or a drainage implant. The gold standard has been trabeculectomy, which can achieve good reductions in IOP. However, this procedure is invasive and has a high complication rate of hypotony, leaky and/or failed blebs and endophthalmitis. For those patients less likely to benefit from trabeculectomy, a tube-shunt surgery may be more suitable.

NICE has published guidance on the diagnosis and management of chronic open angle glaucoma and ocular hypertension in April 2009.

4.1 NEW APPROACHES

Drug delivery systems

Compliance with long term eye drop treatments is a great problem in glaucoma management. Novel drug delivery systems have the potential to address this issue. A number of companies are developing long-acting, sustained release versions of drugs already licensed or in development. These have a real potential to improve patient care and clinical outcomes by ensuring that patients with glaucoma consistently receive the drugs they need to avoid progression of their disease. Ideally a drug delivery system for glaucoma would offer a sustained release of the drug for 3-4 months in a single application in a clinic (i.e. non-surgical) setting. The 3-4 month drug release period would fit in with the recommended intervals for a glaucoma check-up.

Targeting new therapeutic sites

New drugs have the potential to target novel therapeutic sites in the eye which can synergistically lower IOP when used in combination with other eye drops. A new class of IOP lowering drugs is being developed which has a dual mechanism of

http://www.nice.org.uk/nicemedia/live/12145/43839/43839.pdf

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action acting through Rho-kinase inhibition and norepinephrine inhibitors. Research is looking at combining this fixed dose combination with a prostaglandin analogue that would provide three mechanisms of actions in a single eye drop. This could potentially have a significant impact on some patients by reducing the number of daily eye drops they use and therefore increasing compliance.

Neuroprotection

Although reduction of IOP has been an effective measure for the majority of glaucoma patients glaucoma is a disease which is characterised by damage to the optic nerve and so it would seem that nerve protecting (neuroprotective) drugs would be beneficial. The development of such medication is an important area of glaucoma research. In glaucoma, neuroprotection offers a method for preventing the irreversible loss of retinal ganglion cells and their axons and is most likely to be used in conjunction with IOP lowering therapies. However there are several unsolved issues related to using neuroprotective drugs. These include the side effects when administered systemically and also the difficulty in delivering the neuroprotective drug to the target tissues. Neuroprotection may be a promising treatment in the future but currently it is still in the early stages of research.

Gene therapy

One of the major challenges of glaucoma is early detection of disease. Biomarkers which allow identification of patients at risk of developing optic nerve damage are being investigated. There are several potential gene therapy targets which could play a role in the future treatment of glaucoma but research is at an early stage.

Minimally invasive glaucoma surgery (MIGS)

Surgical treatment is currently often reserved for glaucoma patients in whom both medical and laser therapy has failed. However, with the development of new devices and techniques of MIGS, many clinicians believe earlier surgical intervention may be more beneficial to the patient as it bypasses issues with eye drop compliance and their associated side effects and the need for continual IOP control. MIGS causes minimal trauma to surrounding tissue so giving a safer operation with a low complication rate and more rapid postoperative recovery of patients compared with traditional filtering surgery.

4.2 NEW TECHNOLOGIES IDENTIFIED

We identified 22 new technologies in development for the treatment of glaucoma. This included pharmaceuticals, laser therapy, ultrasound therapy and surgically implanted devices.

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4.2.1 PHARMACEUTICALS

Long acting/sustained release drugs

Allergan are developing a sustained release version of two licensed drugs - brimonidine and bimatoprost. The drug delivery system is currently in phase II trials. No further information is yet available.

Psivida are developing Durasert™ which is a biodegradable implant that is inserted under the scleral conjunctiva to provide long-term sustained release of latanoprost. No information on the developmental status of this technology is yet available. Another latanoprost ocular drug insert is in development by Aerie pharmaceuticals and is currently entering clinical trials.

Neuroprotective agents Bosch and Lomb are developing BOL-303259-X, a nitric-oxide donating prostaglandin F2-alpha analogue. BOL-303259-X may have the ability to reduce IOP as well as providing a neuroprotective function. BOL-303259-X is currently in phase III trials. No further information about trials and licensing plans is yet available.

Preservative free formulations

The preservatives used in eye drops to treat glaucoma can aggravate dry eye and ocular surface disease and cause symptoms such as burning, itching and watery eyes. This may be less of a concern when topical eye drugs are used in the short term but it is problematic when used long term as is the case for many patients with

Expert opinion: Theoretically neuroprotection is an exciting concept; however there is still no strong evidence to suggest that it is effective in reducing visual loss. This evidence may actually be difficult to obtain in the relatively short timeframe of a clinical trial with relatively few participants. Prostaglandins are already widely available and used, and clinical evidence to show that BOL-303259-X provides the additional benefits of neuroprotection is required before it is known whether it will have a significant impact on the care pathway.

Expert opinion: The emergence of long acting or sustained release versions of licensed drugs for glaucoma will be an innovative and important step in drug delivery and has the potential to circumvent patient compliance issues especially in the elderly and therefore improve clinical outcomes. Their use may be constrained by cost pressures in the NHS.

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glaucoma. Allergan are developing preservative free formulations of already licensed drugs bimatoprost (Lumigan®) and timolol/bimatoprost and Thea are launching preservative free latanoprost. This will provide an additional treatment option for patients sensitive to preservatives. In addition given that compliance is an important issue in glaucoma, a more comfortable topical formulation may improve treatment adherence and subsequently treatment effects. Tafluprost, a preservative free prostaglandin is already licensed for use in the UK.

Combination therapy of licensed dugs Brimonidine 0.2%/brinzolamide 1% ophthalmic suspension (eye drops) is a new combination therapy of two licensed drugs developed by Alcon Inc for the treatment of glaucoma. The company describes the key differentiator of this product as the first fixed combination glaucoma medication without a beta-blocker, enabling maximum drug combination therapy. Although prostaglandin analogues are considered a reasonable first-line treatment choice this new drug combination therapy may provide an alternative treatment option.

Rho-kinase inhibitors

A new class of drugs for glaucoma called Rho-kinase inhibitors acts directly on the cells of the trabecular meshwork to improve aqueous outflow and restore the eye’s natural drainage pathway. This is a novel target and approach to lowering IOP that is in development at a number of companies.

Expert opinion: This drug therapy may be an option for the elderly and patients with asthma and chronic obstructive pulmonary disease where the clinician wishes to avoid using beta blocking drugs. However, given the high likely allergy rate of this combination therapy it is unclear what the full benefits may be for this patient group.

Expert opinion: Preservative free eye drops will be a major growth area in the future of glaucoma management and have a role in patients who experience uncomfortable side effects associated with preservatives. The increased cost of preservative free eye drops compared to eye drops containing preservatives is substantial and is the main barrier for wider adoption. Eye drops containing less irritating preservatives i.e. benzalkonium chloride are available and may be another option for these patients.

http://www.alcon.com/en/

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Aerie Pharmaceuticals are developing the lead compound in this class, AR-12286 which is currently in phase II trials. They are also investigating AR-12286 in combination with travoprost which is currently in the pre-clinical phase. Altheos are also developing ATS90 but they have no plans to market in the UK.

4.2.2. LASER TREATMENT

Selective laser trabeculoplasty (SLT) is being increasingly used as primary treatment in some glaucoma patients due to its safety profile. With the lack of thermal and structural damage to the surrounding cells, SLT is increasingly being used in preference to conventional argon laser trabeculoplasty. Furthermore SLT can be repeated if future re-treatment is required.

There are three new and emerging lasers in development for glaucoma.

Titanium sapphire laser trabeculoplasty (TSLT)

Titanium sapphire laser trabeculoplasty is in development by SOLX for the treatment of open angle glaucoma. A sapphire laser emits energy at a near-infrared 790nm wavelength in pulses lasting five to 10 microseconds. The longer wavelength, compared to SLT, can deliver more energy per pulse and possibly penetrate deeper into the tissue, which may provide additional treatment benefits.

No further information including CE mark and launch plans is yet available.

Micropulse diode laser trabeculoplasty

Micropulse diode laser trabeculoplasty (MDLT) developed by Iridex is a compact, portable laser, which emits a series of short, repetitive, low-energy pulses separated by a rest period to allow the tissue to cool between pulses. The short pulses are claimed to reduce the diffusion of thermal heat from the laser to adjacent tissue. Like

Expert opinion: TSLT is an incremental development to SLT which is already widely available. Further trials are required to compare TSLT with SLT to determine whether it is superior to an already established technology and if it is worth the extra investment in new equipment.

Expert opinion: Rho-kinase inhibition is a new mechanism of action and is a novel approach to lowering IOP so this group of drugs may add a major new method of IOP lowering treatment. There is the potential for further IOP lowering when used in combination with other drugs.

http://www.solx.com/http://www.iridex.com/

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SLT, minimal damage to the adjacent trabecular meshwork may mean this is an attractive option to treat patients with glaucoma.

MDLT has been CE marked for several years but is not yet widely adopted in the NHS. A small number of UK centres are using MDLT; however clinical trials comparing MDLT to SLT are still required to determine its comparative effectiveness. The portable nature of MDLT and its apparent low side effect profile could enable it to have a place in a non-surgical setting.

IOPtiMate™

IOPtiMate™ developed by IOPtima Ltd is an innovative surgical system performing non-penetrating deep sclerectomy for glaucoma patients. A CO2 laser locally thins the scleral wall around the Schlemm’s Canal in the eye and reduces IOP by filtering intra-ocular fluid from the anterior chamber through the remaining intact membrane. It is a self-regulatory procedure where the laser automatically stops, preventing further tissue ablation, once it comes in contact with sufficient intra-ocular percolating fluid. The eyeball is kept intact, and may reduce complications commonly experienced with trabeculectomy, which involves full thickness penetration.

The IOPtiMate™ was CE marked in 2009 but is not currently being used in the UK.

Expert opinion: CO2 laser assisted sclerectomy surgery is more accurate than trabeculectomy but whether the stated benefits are better than trabeculectomy is uncertain. Sclerectomy surgery is technically very challenging but the CO2 laser helps alleviate this problem. Given the relative reluctance to perform non-penetrating surgery in the UK and the cost of the equipment, this modality of laser assisted surgery is unlikely to gain popularity here.

Expert opinion: MDLT is unlikely to be an important innovation in the UK unless results are dramatically better than SLT and the extra investment in new equipment can be justified clinically.

http://www.ioptima.co.il/

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4.2.3 ULTRASOUND

Therapeutic ultrasound is an innovative method for the management of glaucoma, although it is not currently available. We identified two ultrasound devices in development for glaucoma.

Therapeutic Ultrasound for Glaucoma (TUG)

TUG, developed by EyeSonix, provides a new non-invasive method of treatment for open angle glaucoma and ocular hypertension. The device applies a low power, low frequency ultrasound of 40 KHz, to the outside of the eye just adjacent to the limbus. It is applied sequentially at “clock hours” around the limbus for 45 seconds at each clock hour. This creates a localised area of hyperthermia and may induce a similar cytokine release to that of laser applied to the trabecular meshwork of the eye and thereby lead to a decrease in IOP. The treatment is repeatable and would last approximately 6 months. The company claims that in over 70% of patients treated with TUG the treatment effect has lasted for over a year for the clinical control of IOP.

TUG can be used as an initial treatment option in patients with newly diagnosed glaucoma or as an adjunct in patients already on medication or as a means of reducing the number of medications needed to control IOP.

TUG expects to receive a CE mark within the next 12 months.

EyeOp1®

The EyeOP1® device has been developed by EyeTechCare for the treatment of glaucoma that is resistant to other therapies. A disposable probe is placed on the eyeball and held in place by suction. Ultrasound waves are then delivered to the

Expert opinion: TUG is an innovative method of treating glaucoma by reducing the production of aqueous humour. Cyclodiode laser ablation is the comparator device which is used in severe glaucoma and can be quite traumatic to the eye. If TUG is proved to be less traumatic it could be used earlier in the treatment pathway in an outpatient setting. However TUG must be evaluated fully and compared against cyclodiode laser ablation to prove it is equally effective. There is the potential for TUG to become a popular treatment choice if it can demonstrate a very good safety profile and be made available at an appropriate cost to the NHS.

http://eyesonix.com/http://www.eyetechcare.com/

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ciliary body via transducers (devices that convert one form of energy into another) in the probe. The ultrasound heats the ciliary body and selectively destroys it to decrease the production of aqueous humour. Ultrasound does not affect prospective drug or surgical treatments and EyeOP1® does not depend upon pigment in the ciliary to work effectively. The procedure is performed under local anaesthetic and lasts less than three minutes with the patient able to go home the same day. The company claim that the learning curve to using EyeOP1 is very short. Its use may also not be limited to use in the operating theatre but include use in clinic/outpatient settings too.

The EyeOP1® control module costs £47,995 plus VAT and the EyeOP1® pack single use costs £650 plus VAT. The EyeOP1® device was CE marked in May 2011 but is not yet available in the UK. A restricted EU launch was planned in the third quarter of 2012. The NIHR Horizon Scanning Centre has completed a briefing for EyeOp1®.

4.2.4 SURGERY

Minimally invasive procedures are in development as alternatives to trabeculectomy. These are classified as ab-interno (from the inside) or ab-externo procedures (from the outside).

Minimally invasive glaucoma surgery

Ab-interno approaches

Trabectome®

The Trabectome® has been developed by Neomedix, for the surgical treatment of open angle glaucoma. The Trabectome® hand piece is a one-use disposable device that is bent 90° as it ablates and removes a 60°-120° strip of trabecular meshwork

Expert opinion: Like TUG, there is little evidence comparing EyeOP1® to its competitor - diode laser cycloablation which has a positive evidence base. However, it is less invasive and is performed under local anaesthetic so the procedure can be performed on an outpatient basis which may potentially bring significant savings in NHS resources. As above, to be adopted widely EyeOp1® must demonstrate a very good safety profile and be made available at an appropriate cost to the NHS.

http://www.hsc.nihr.ac.uk/topics/eyeop1-for-glaucoma/http://www.neomedix.net/

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creating a cleft and re-establishing access to the eye’s natural drainage pathway. Simultaneous irrigation maintains a constant pressure in the eye and deepens the anterior chamber and aspiration removes particles of trabecular meshwork and residual heat.

The Trabectome® according to the company is available for use in the NHS but at only one specialised centre – the Royal Hallamshire Hospital in Sheffield. It is a very innovative surgical procedure which targets the trabecular meshwork directly. In comparison to trabeculectomy it is minimally invasive, less surgical time in the eye is required, there are fewer postoperative complications such as the creation of a subconjunctival bleb and patient recovery is quicker. The capital cost of the trabectome system is £24,451 and per case/procedure pack (based on quantity) is £254-£421.

The Trabectome® was CE marked in 2009. NICE has published guidance on the use of trabeculectomy ab-interno for open angle glaucoma in May 2011.

Hydrus™ Microstent

The Hydrus™ Microstent is being developed by Ivantis Inc for the treatment of primary open angle glaucoma. The Hydrus™ Microstent is made from nitinol, a flexible nickel titanium alloy. The crescent-shaped, non-luminal 8.0mm long hydrus implant is a scaffold intended to re-establish the patient’s conventional outflow pathway by dilating Schlemm’s canal. It is placed into the eye through a minimally invasive, microsurgical procedure. The Hydrus™ Microstent comes preloaded in a disposable injector system and it is implanted through a 1.0mm to 1.5mm incision into Schlemm’s canal. The procedure can be carried out at the same time as cataract surgery using the same microsurgical incisions. As it is a minimally invasive procedure it has fewer complications and a faster post-operative recovery time than trabeculectomy.

The Hydrus™ Microstent is not available for clinical use in the NHS but it is being trialled at the Birmingham Midland Eye Centre. Hydrus™ Microstent is CE marked but no further information is yet available.

Expert opinion: The Trabectome® is intended to be used in mild/moderate glaucoma patients and is unlikely yet to have a major impact in advanced glaucoma patients. Further evidence is required comparing the effectiveness of Trabectome® to trabeculectomy before clinicians will have confidence in using this new technology in severe cases of glaucoma. Training will be required and there will inevitably be a learning curve for new operators. NHS resource impact would also be high since an initial outlay cost of buying the device is required.

http://www.nice.org.uk/nicemedia/live/13048/54514/54514.pdfhttp://www.ivantisinc.com/

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iStent® Trabecular Micro-Bypass Stent

The iStent® has been developed by Glaukos for the reduction of IOP in patients with mild to moderate open-angle glaucoma who are unable to achieve adequate control using medical therapy alone and undergoing cataract surgery. It is a heparin-coated implant measuring 0.5 x 1.0mm and is the first CE marked device to create a permanent opening into the trabecular meshwork. Implantation of the stent into Schlemm's canal allows aqueous humour to drain directly from the anterior chamber into Schlemm's canal bypassing the obstructed trabecular meshwork. By preserving the trabecular meshwork the risk of hypotony (low IOP) is also minimised. The procedure is performed ab-interno sparing the conjunctival space which preserves the potential for future treatment.

The iStent® was CE marked in 2004 and FDA approved in 2012. It is currently being used in a few specialist centres in the UK.

NICE has published guidance on the use of trabecular stent bypass microsurgery for open angle glaucoma in May 2011.

Expert opinion: The iStent® is an innovative device which targets the site of disease. The main advantage of the iStent® is that it is inserted at the same time as cataract surgery therefore hospitals already performing cataract surgery are unlikely to face significant operational changes. However training will be needed and there is an inevitable learning curve when a new operator uses the device. The cost of the device may be a barrier to adoption into clinical practice and more data is required on long term cost effectiveness. It is likely that the IOP reducing potential would be further improved by the implantation of two stents instead of one.

Expert opinion: The likely patient and clinical impact of the Hydrus™ Microstent may be significant if this procedure is performed earlier in the pathway than current surgical options, allowing the elimination or reduction of the need for daily eye drops. However surgeons would need to be trained in its use and there would be an associated learning curve. Long term data is required to determine its effectiveness and identify which patients would benefit most from this procedure. The Hydrus™ Microstent is a direct comparator to the iStent®. Like the iStent®, the cost of the device may be a barrier to adoption into clinical practice.

http://www.glaukos.com/http://www.nice.org.uk/nicemedia/live/13157/54571/54571.pdf

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Xen® Glaucoma Implant

The Xen® glaucoma implant in development by Aquesys is a soft natural collagen-derived gelatin implant, which is implanted at the same time as cataract surgery or as a standalone procedure in patients with mild glaucoma. It uses an ab-interno approach to access the subconjunctival space – an area most commonly accessed via ab-externo methods. The implant bypasses the trabecular meshwork and creates a new pathway for fluid drainage out of the eye to reduce IOP. The conjunctiva is not disrupted using this method and the site can be re-treated in the future if needed. The gelatin material is claimed to be non-inflammatory.

The advantage of the Xen® implant is that it may be less traumatic than trabeculectomy. It is a simple and quick procedure taking as little as ten minutes to perform. Postoperative complications may be fewer in number and patient recovery faster.

The Xen® implant is currently in clinical trials but no further information including CE mark and launch dates were available from the company.

Cypass Micro-stent®

The Cypass Micro-stent® in development by Transcend Medical is a polyamide tubular stent designed to shunt aqueous humour from the anterior chamber to the suprachoroidal space. This allows a controlled outflow path into the suprachoroidal space minimising risk of hypotony. This technique has the benefits of an ab-interno approach and the potential to significantly reduce IOP levels to even below episcleral levels. It is intended to be used in patients with mild to moderate glaucoma requiring cataract surgery.

The Cypass Micro-stent® was CE marked in 2009 but no further information on cost or usage in the UK is yet available.

Expert opinion: Xen® is an interesting device which creates an artificial pathway using a minimally invasive ab-interno procedure. However, there may be an increased chance of fibrosis of surrounding tissue and hypotony which may limit the potential value of this technology in the future of glaucoma management.

http://aquesys.com/http://www.transcendmedical.com/

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Ab-externo approaches

SOLX® gold shunt

The SOLX® gold shunt is being developed by SOLX, Inc for the treatment of refractory glaucoma. The SOLX® Gold Shunt is a pure gold, miniature, flat drainage device designed for surgical implantation in the eye. When implanted, the SOLX® Gold Shunt allows drainage of aqueous fluid from the anterior chamber to the suprachoroidal space. The company state that it is the first device to reduce IOP without creating a filtering bleb.

The SOLX® Gold Shunt has been CE marked since October 2005 but is not available in the NHS in England and Wales. The company plan to launch into the UK market in early 2013.

iTrack™ Canaloplasty Microcatheter

The iTrack™ Canaloplasty Microcatheter in development by iScience Interventional is a device which facilitates the reduction of IOP by enlarging Schlemm’s canal. A prolene suture is threaded through Schlemm’s canal using a microcatheter and viscoelastic to dilate the canal. The suture is held tight to keep the canal open. Canaloplasty addresses the outflow obstructions and is claimed that physiologic flow is more likely to be restored compared to methods that bypass the trabecular meshwork. The procedure works without the need to create a filtering bleb which is often associated with several postoperative complications such as scaring, leaky blebs and hypotony.

Expert opinion: Like the Cypass Micro-stent®, fluid drainage into the suprachoroidal space allows for a significant reduction in IOP but this holds an increased risk of hypotony. Suprachoroidal devices tend to scar down, therefore there is potential to use it with anti-scarring treatment. Like the Cypass Micro-stent® more research evidence on effectiveness and cost effectiveness is required before it can be considered for routine use in the NHS.

Expert opinion: The Cypass Micro-stent® appears to be very innovative as it allows significant fluid drainage into the superchoroidal space which can allow lowering of IOP to very low levels. However this may bring an increased risk of hypotony and there is the potential for fibrosis of the surrounding tissue. More research evidence on effectiveness and cost effectiveness is required before it can be considered for routine use in the NHS.

http://www.solx.com/http://www.iscienceinterventional.com/

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No further information including CE mark and launch dates was available from the company.

NICE published guidance on canaloplasty for primary open-angle glaucoma in May 2008.

Expert opinion: Canaloplasty is very effective at lowering IOP with minimised postoperative complications but it is a technically difficult procedure to perform, which may limit its uptake. The ab-externo approach is usually less favoured compared to ab-interno methods.

http://www.nice.org.uk/nicemedia/live/11911/40769/40769.pdf

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5. REFERENCES 1. Medline Plus. Glaucoma. http://www.nlm.nih.gov/medlineplus/ency/article/001620.htm

Accessed 7 November 2012. 2. NHS Choices. Glaucoma.

http://www.nhs.uk/Conditions/Glaucoma/Pages/Introduction.aspx Accessed 8 November 2012.

3. National Institute for Health and Clinical Excellence. Glaucoma: diagnosis and management of chronic open angle glaucoma and ocular hypertension. Clinical guideline CG85. London: NICE; April 2009.

4. National Institute for Health and Clinical Excellence. Glaucoma: diagnosis and management of chronic open angle glaucoma and ocular hypertension. National Costing Report. Implementing NICE Guidance. London: NICE; April 2009.

5. Aptel F, Charrel T, Lafon C et al. Miniaturized high-intensity focused ultrasound device in patients with glaucoma: a clinical pilot study. Investigative Ophthalmology & Visual Science. Published online first: 22 September.

6. NIHR Horizon Scanning Centre. http://www.hsc.nihr.ac.uk/ 7. The International Information Network on New and Emerging Health Technologies.

http://euroscan.org.uk/

http://www.nlm.nih.gov/medlineplus/ency/article/001620.htmhttp://www.nhs.uk/Conditions/Glaucoma/Pages/Introduction.aspxhttp://www.hsc.nihr.ac.uk/

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APPENDICES

APPENDIX 1

Detailed methods

The review was carried out between May 2012 and November 2012. The methodological steps were:

1: Recruiting experts

Key experts in the field of glaucoma were recruited and their agreement sought in suggesting new technologies and prioritising technologies the NIHR HSC identified.

2. Protocol development

A protocol was agreed which outlined the inclusion criteria for technologies to be considered in the review. This included;

• Pharmaceuticals that were within 24 months of licensing • Medical technologies that were:

o emerging’ - expected to be CE marked (where appropriate) or launched within the UK in the next 24 months

o ‘new’ - CE marked (where appropriate) and has usually only been available for clinical use for ≤12 months and is generally in the launch or early post-marketing stages.

o ‘new and poorly adopted’ – medical technologies that are within 2 years post launch and poorly (

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• Clinica for intelligence on medical technologies for glaucoma. • Google for general information.

Experts were also asked to suggest new and emerging glaucoma technologies known to them.

4. Compiling information about identified technologies

Identified technologies with an unknown status or those that fitted the remit were investigated further. Companies were contacted by email and telephone to collect further information for their products licensing status, availability, novelty, description of technology, cost and clinical evidence. Companies that did not respond were contacted at least twice more by email and/or telephone. Where companies did not respond, publicly available information on technologies was sought.

5. Expert comment upon identified technologies

For each identified technology, expert comment was sought on the potential impact of the identified technologies and their place in the care pathway.

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APPENDIX 2

Table 1: Technologies excluded from review

Technology Purpose of technology Reason for exclusion

AZD4017; Astrazeneca Treatment (medical) Not enough publicly available information to determine novelty and potential impact.

SYL040012;Sylentis Treatment (medical) Marketing Authorisation Application outside of NIHR HSC timeframe.

K115; Kowa Pharmaceuticals Treatment (medical) Not enough publicly available information to determine novelty and potential impact.

OPA-6566; Acucela and Otsuka Pharmaceutical Treatment (medical) No plans to license in Europe.

Y39983; Alcon Treatment (medical) Not an active R&D project. Not developing for commercial launch.

AL-54478; Novartis Treatment (medical) Discontinued.

INO 8875; Inotek Pharmaceuticals Treatment (medical) Not enough publicly available information to determine novelty and potential impact.

Cf-101; Can Fite BIoPharma Ltd Treatment (medical) Not enough publicly available information to determine novelty and potential impact.

Latanoprost Punctal Plug Delivery System; QLT inc.

Drug delivery system Company divesting in this area.

Scleral Implant – 9G-AHF; 9 glens Treatment (surgical) Not enough publicly available information to determine novelty and potential impact.

CONTENTSExECUTIVE sUMMARYACKNOWLEDGMENTS1. INTRODUCTION1.1 CLINICAL NEED AND BURDEN OF DISEASE1.2 AIM & objective2. Methods3. DIAGNOSIS AND MONITORING IN GLAUCOMA3.1 NEW APPROACHES3.2 New technologies identified3.2.1 Measuring IOP3.2.2 Visual field test3.2.3 Optic nerve and retinal nerve fibre layer assessment

4. TREATMENT OF GLAUCOMA4.1 New approaches4.2 NEW TECHNOLOGIES IDENTIFIED4.2.1 Pharmaceuticals4.2.2. Laser treatment4.2.3 Ultrasound4.2.4 Surgery

5. ReferencesAppendicesAppendix 11: Recruiting experts2. Protocol development3. Identifying new and emerging technologies4. Compiling information about identified technologies5. Expert comment upon identified technologies

Appendix 2