Ophthalmology Clinical Research: The India Advantage

1. Ophthalmology Clinical Research: The India Advantage

2. Points of discussion

3. Ophthalmic market The market in India

4. Ophthalmology market: India Ophthalmology market in India is at the forefront of a new revolution • Out of the seven Joint Commission International (JCI) accredited hospitals in India, one is an eye hospital. • Recently, an eye hospital from South launched its first Initial Public Offering (IPO) which was fully subscribed • Ophthalmology in India has evolved to be one of the most sought after destinations, Under health tourism. • Technology boom: Newer diagnostic modalities & high tech equipment have enabled ophthalmologists http://www.modernmedicare.in/article/Evolving-Ophthalmology/page1.html

5. Ophthalmology market: India • New generation of informed patients • Indian ophthalmology sector is well supported by a number of accomplished eye care centers. • Strong network of tertiary care institutes both in public and private sectors has proved to be India’s strength in this segment • Refractive treatments are gaining popularity, both among the public as well as among ophthalmologists.

6. Ophthalmic Device Market: India • The ophthalmic medical device sector can be organized into three major segments • Diagnostics • Cataract surgery products, including intraocular lenses, viscoelastics, & phacoemulsification systems • Refractive surgery products, including excimer and femtosecond lasers, microkeratomes, and usage-based procedure cards. • In addition to devices, the ophthalmic market includes pharmaceuticals and eye-care products such as contact lenses and solutions.

7. Ophthalmic Device Market • The worldwide ophthalmic products market exceeds $22 billion & is growing at >10% per year. • Not counting consumer eye-care products, the ophthalmic products market reached an estimated $17 billion in 2006. • Ophthalmic device market in India remains fairly fragmented • Multinational firms have immense presence in some segments • Some of the key players in this segment are Advanced Opthalmic Imaging System, consolidated Products Corp. Pvt. Ltd., Bausch & Lomb, Carl Zeiss, J&J vision care. Appasamy Associates, Mehra Eyetech Pvt. Ltd., Toshbro Medicals,

8. Ophthalmic Diseases Clinical Scenario in India

9. Corneal transplantation, also known as corneal grafting or penetrating keratoplasty According to Indian council of Medical Research (ICMR) study on blindness, about 25% of the total blind in India are blind due to corneal blindness The number of Corneal Blinds in India are about 4.60 Million In India, there is no dearth of knowledge, skills and resources to create a world class eye banking and corneal transplantation network Corneal transplantation in India

10. Corneal transplantation: Potential centers in India* *Based on telephonic discussion with potential investigators

11. Diabetic Macular Edema (DME) • Definition of DME: swelling of the retina in diabetes mellitus due to leaking of fluid from blood vessels within the macula1 • Macular edema is common in diabetes with a lifetime risk of 10%1 • The condition is closely associated with the degree of diabetic retinopathy • Clinically Significant Macular Edema (CSME), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), includes any of the following findings2,3 • Retinal thickening within 500 µm of the center of the fovea • Hard, yellow exudates within 500 µm of the center of the fovea with adjacent retinal thickening • At least 1 disc area of retinal thickening, any part of which is within 1 disc diameter of the center of the fovea Source: 1” Definition of Diabetic macular edema”, MedicineNet.com Website Accessed on May 12, 2009, 2“Macular Edema, Diabetic”, emedicine Website Accessed on May 12, 2009, 3“International Clinical Classification of Diabetic Retinopathy, Severity of Diabetic Macular Edema, Detailed Table”, International Council of Ophthalmology, October 2002

12. DME Prevalence Estimates for 2009 Population of India1 (1,197M) Diabetic patients2: 36.4M CSME (Based on Study 1) CSME (Based on Study 4) 2.18M (6% of diabetic patients) 1.41M (3.9% of diabetic patients) Worksheet Worksheet • Assumption: type 1 diabetes constitutes a negligible proportion of the total diabetics • The prevalence of type 1 diabetes is 0.01%3 • Prevalence rate of CSME among diabetic patients (based on the above assumption): 6% (Study 1) • Assumption: the prevalence of DME in diabetic patients < 30 years of age is negligible* • Adjusting the prevalence rate of CSME to all age group (Study 4) • Prevalence of CSME in diabetic patients > 30years: 4.1% • The above-mentioned prevalence rate was adjusted considering the assumption and accounting for additional prevalent patient pool to make up for all age group4 • Adjusted prevalence rate (all age group) is 3.9% *Considering the fact that the mean age of patients with DME has usually been > 50 years in many studies Source: 1United Nations population Division Website Accessed on May 12, 2009, 2Sarah Wild et al (2004), “Global Prevalence of Diabetes”, Diabetes Care 2004; Vol. 27:1047–1053 3Pushpa Krishna et al (2005), “Dyslipidemia in Type 1 Diabetes Mellitus in the Young”, International Journal of Diabetes in Developing Countries 2005;Vo1 25 (4):110-12, 4Anil J Purty et al (2009), “Prevalence of Diagnosed Diabetes in an Urban Area of Puducherry, India: Time for preventive action”, Int J Diab Dev Ctries 2009;29:6-11

13. Prevalence – DME/CSME (1/2) Source: 1Sunil Gupta (2004), ”Prevalence of Diabetic Retinopathy and Influencing Factors Amongst Type 2 Diabetics from Central India”, Int. J. Diab. Dev. Countries 2004; Vol. 24:75-78, 2Ramachandran A et al (2000), “Vascular Complications in Young Asian Indian Patients with Type 1 Diabetes Mellitus”, Diabetes Res Clin Pract. 2000 Apr;48(1):51-6, 3V Narendran et al (2002), “Diabetic retinopathy among self reported diabetics in southern India: a population based assessment”, Br J Ophthalmol 2002;86:1014–1018

14. DME – Treatment Flow (PMR, India) N=2 DME patients constitute 90% of the Macular Edema patients Diabetic Macular Edema (DME) – 100% Clinically Significant Macular Edema (CSME) - 40% Clinically Insignificant Macular Edema – 60% Focal Macular Edema (FME) – 60% Diffuse Macular Edema (DiME) – 40% Focal CSME – 40% of FME Diffuse CSME – 40% of DiME • Irrespective of severity, CSME patients would be administered treatment • Sometimes, physicians may also treat clinically insignificant DME (Intravitrealanit-VEGF and laser treatment on deterioration) CSME Treatment First-line of therapy – 100% Second-line of therapy – 25%-30% Third-line of therapy – 5% • Focal Macular Edema • Focal laser treatment • Diffuse Macular Edema • Grid laser treatment • Focal Macular Edema • Intravitreal steroids and anti-VEGF (AVASTIN) • Focal laser treatment • Diffuse Macular Edema • Intravitrealsteroidsand anti-VEGF (AVASTIN) • Grid laser treatment • Focal Macular Edema • Vitrectomy • Diffuse Macular Edema • Vitrectomy Source: KOL interviews

15. Glaucoma • Glaucoma represents a heterogeneous group of optic neuropathies and is estimated to affect 12 million Indians; it causes 12.8 per cent of the total blindness in the country and is considered to be the third most common cause of blindness in India • An Asian survey presented at the World Ophthalmology Congress in Hong Kong in July 2008 revealed that between 2010 and 2020, India will be the world’s glaucoma capital. • Primary angle-closure glaucoma (PACG) is a major form of glaucoma in Asian countries.According to an Indian hospital-based data, PACG appears to be as prevalent as primary open-angle glaucoma (POAG), accounting for 45- 55% of primary glaucoma cases. Henson DB, Thampy R. Preventing blindness from glaucoma. BMJ. 2005; 331 Suppl 7509:120-1 Chew PT, Aung T. Primary angle-closure glaucoma in Asia. Journal of Glaucoma 2001;5 Suppl 1:S7-S8

16. Glaucoma – treatment • Since the disease is not curable early detection and prevention are the key focus areas, however, surgery and laser treatment do appear to be promising • Treatment includes - glaucoma surgeries • trabeculectomy - the procedure of choice particularly for secondary glaucomas. • Various new modalities - mini trab procedure ,non penetrating filtering procedure, trans ciliary filtering’ surgery in 2004, ‘limbal filtering’ surgery in 2006 using a fugo plasma blade. • Newer glaucoma surgeries (non-penetrating) like deep sclerectomy, viscocanalostomy and trabeculectomy ab-externo have also shown promising results.

17. Glaucoma treatment - latest procedures • Cyclocryotherapy for ciliary body ablation helps reduce the eye pressure and alleviate pain. • Glaucoma implants have been used for patients who are not responding to maximal medical therapy or are failed glaucoma surgery or poor candidates for glaucoma surgery. • Selective Laser Trabeculoplasty (SLT) • Ciliary body diode laser cycloablation • Nd:YAG Laser peripheral iridotomy

18. Refractive errors • Refractive errors (myopia, hypermetropia, astigmatism, presbyopia) result in an unfocussed image falling on the retina. • Uncorrected refractive errors, which affect persons of all ages and ethnic groups, are the main cause of visual impairment. • There are estimated to be 153 million people with visual impairment due to uncorrected refractive errors, i.e. presenting visual acuity < 6/18 in the better eye, excluding presbyopia. • Globally, uncorrected refractive errors are the main cause of visual impairment in children aged 5–15 years. The prevalence of myopia (short-sightedness) is increasing dramatically among children, particularly in urban areas of South-East Asia.

19. Refractive vision correction • The most frequently used options for correcting refractive errors are: • spectacles, the simplest, cheapest and most widely used method; • contact lenses, which are not suitable for all patients or environments; • corneal refractive surgery, which entails reshaping the cornea by laser.

20. Trends in refractive vision correction • The path to refractive corrections for myopia, hyperopia, presbiopia and astigmatism is pitted with technologically sound techniques • Broad range of options to treat each patient’s unique needs • LASIK, Laser-Assisted Sub-Epithelial Keratectomy (LASEK) • clear lens exchange (CLE), • phakic intraocular lenses (PIOL), and • conductive keratoplasty (CK)

21. Age Related Macular Degeneration (ARMD) • Age-related macular degeneration is the commonest cause of blindness in industrialized countries. • Age-related macular degeneration has two forms, ‘wet’ and ‘dry’. In most populations, the dry form is the more frequent, but it is less likely to lead to severe bilateral visual loss. • Age-related macular degeneration is responsible for 8.7% of all blindness (3 million persons) due to eye diseases, ranging from close to 0% in sub-Saharan Africa to 50% in industrialized countries. • The number affected is expected to double by the year 2020 as a result of the ageing of the world’s population.

22. Upcoming trends in the treatment of ARMD • Photodynamic therapy (trade name Visudyne) uses a non-thermal (or cold) laser with an intravenous light-sensitive drug to seal and halt or slow the progression of abnormal retina blood vessels. • LASER photocoagulation is a procedure involving the application of a hot laser to seal and halt or slow the progression of abnormal blood vessels • New anti-vascular endothelial growth factor agents are being investigated, and more research is needed. • Surgical translocation of the macula and submacular surgery are indicated only for selected patients, as surgery requires highly experienced vitreo-retinal surgeons, and the results are not always favourable.

23. Cataract • The most recent estimates from WHO reveal that 47.8% of global blindness is due to cataract • South Asia region which includes India, 51% of blindness is due to cataract • Approximately, nine million Indians are blind from cataract with another 1.8-3.8 million going blind from cataract every year. • Ophthalmologists and programme planners have been able to effectively increase cataract surgical output from a low of 1.2 million surgeries in 1992 to a high of 4.8 million surgeries in 2006 with intraocular lenses (IOLs) used in 90 per cent of cases Indian J Ophthalmol. 2008 Nov–Dec; 56(6): 489–494. “Current status of cataract blindness and Vision 2020: The right to sight initiative in India”

24. Reasons for decreasing in blindness prevalence • 25% decrease in blindness prevalence in India (WHO report) • This could be due to the increased cataract surgeries in the country • Due to factors • indigenous manufacturing of IOLs, • equipment and supplies for cataract surgery, • structured training programmes, • infrastructure development and • co-ordinated efforts by the Government and the international NGOs Murthy GV, Gupta SK, Bachani D, Jose R, John N. Current estimates of blindness in India. Br J Ophthalmol. 2005;89:257–60

25. Uveitis and its Classification Uveitis2 • Uveitis is a potentially blinding intraocular inflammation1 • The inflammation can include iris, ciliary body, choroid, retina, optic nerve and vitreous1 Anterior Uveitis Intermediate Uveitis Posterior Uveitis Pan Uveitis • Location: Iris , ciliary body & cornea • Main Causes: Idiopathic, HLA-B27 association, Trauma, Infection • Location: Peripheral retina, pars plana & vitreous • Main Causes: Idiopathic, Systemic disorders like sarcoidosis, Multiple sclerosis etc • Location: Choroid & Retina • Main Causes: Infections, Systemic disorders • Location: anterior chamber, vitreous, and retina and/or choroid • Main Causes: Infections • Common causes of Uveitis in a 2006-07 study in 475 patients at AIIMS Delhi:3 • 65% no definitive etiology • Systemic disorders: Ankylosing spondilytis, TB, juvenile idiopathic arthritis and sarcoidosis • Ocular disease: Ocular toxoplasmosis • Other: Serpiogenous chorditis, Behcet’s disease, VKH syndrome etc Sources: 1O.M. Durrani et al. “Uveitis: A Potentially Blinding Disease” Ophthalmologica 2004, 2Robert H Janigian Jr “Uveitis, Evaluation and Treatment” emedicine November 2007, 3Dr. Subrata Mandal et al. “Prevalence and Clinico-Epidemiological Profile of Uveitic Blindness” AIOC 2008 PROCEEDINGS

26. Uveitis – Treatment Flow (PMR, India) Treated Uveitis Infective N=2 Antibiotic (15-20%) Non-infective Steroid (100%) Anterior Uveitis (44%) Intermediate Uveitis (16%) Posterior Uveitis (25%) Pan Uveitis (15%) Observation (0-2%) Observation (0%) Acute (95%) Acute (40%) Topical Steroid (90-98%) Chronic (5%) Topical Steroid (100%) Chronic (60%) Acute (40%) Periocular Steroid (5-10%) Acute (40%) Periocular Steroid (10-20%) Chronic (60%) Chronic (60%) Acute (20%) Systemic Steroid (20-25%) Acute (50%) Systemic Steroid (90-100%) Chronic (80%) Immunosuppressant (2-5%) Chronic (50%) Immunosuppressant (2-5%) Cycloplegics (80-90%) Sources: KOL interviews & Secondary estimates

27. Active Uveitis Prevalence Estimates for 2009 Indian population 1,197.2M Numbers in million Base Case Prevalence of Active Uveitis, 0.37% 4.4M Posterior Uveitis 1.11M Pan Uveitis 0.67M Anterior Uveitis 1.92M Intermediate Uveitis 0.71M Downside case Prevalence of Active Uveitis, 0.19% 2.2M Posterior Uveitis 0.57M Pan Uveitis 0.34M Anterior Uveitis 0.99M Intermediate Uveitis 0.36M Upside case Prevalence of Active Uveitis, 0.70% 8.38M Posterior Uveitis 2.1M Pan Uveitis 1.27M Anterior Uveitis 3.65M Intermediate Uveitis 1.35M Note: Weighted average distribution of the studies is considered for the estimation of subtype prevalence: Anterior Uveitis 44%, Intermediate Uveitis 16%, Posterior Uveitis 25% & Pan Uveitis 15%

28. The Right to Sight in India • India was the first country in the world to launch the National Programme for Control of Blindness in 1976 with the goal of reducing the prevalence of blindness. • Of the total estimated 45 million blind persons in the world, 7 million are in India. • Due to the large population base & increased life expectancy, the no. of blind particularly due to age-related disorders like cataract, is expected to increase • Main causes of blindness in 50+ population are cataract 62.6%, refractive errors 19.7%, corneal blindness 0.9%, glaucoma 5.8%, surgical complications 1.2%, posterior segment disorders 4.7%, others 5.0% http://www.who.int/blindness/Vision2020%20-report.pdf

29. Vision 2020: Indian Scenario • India is a signatory to the WHO resolution on Vision 2020: The right to sight • Launched jointly by WHO and the International Agency for the Prevention of Blindness (IAPB) with an international membership of NGOs, professional associations, eye care institutions and corporations • Envisions eliminating the main causes of avoidable blindness by the year 2020 • Programmes will be based on three core strategies • Disease control, • Human resource development and • Infrastructure and technology incorporating the principles of primary healthcare http://www.aios.org/cmefiles/CME_9.pdf

30. Human Resource needs: India Vision 2020: CME series 9 There are >15000 trained ophthalmologists in India

31. Clinical Profile of Institutions in India Based on survey with 128 medical institutions offering training

32. The Clinical Trial Space Scenario in India

33. Growth in clinical research • Outsourced Clinical Drug Trials increasing in number and complexity • 2001 – 2005 : 178% growth in number • Varied motivators • Rapid patient accrual • Medical expertise • Regulatory, Ethical & Industrial infrastructure • GCP mandated by legislation • Evolving clinical research regulatory framework • Product patents

34. Regulatory and Ethics Committee • New guidelines released for “requirements for the manufacture, import and sale of medical devices” in 2009 will pave way growth in this area. • Recent examples of approving the products for marketing based on the Global CT data has created an interest in global players. However, a clear justification & data supporting MAA and a substantial sample of Indian subjects have to be enrolled in the Global CTs. • Regulatory timelines for CT approvals are 45 days • ECs timelines range from 15 days to 2 months • EC working procedures defined by local regulatory framework (Schedule Y)

35. Regulatory Environment: General classification The Figure shows increasing levels of regulatory requirements as the device risk class increases

36. Institutional infrastructure • Specialized institutions in the ophthalmology segment (eg. Sankara Nethralay- Chennai, LVPEI – Hyderabad, Aravind – Madurai) • Institutional ethics committee complying with ICH GCP & Schedule Y requirements • Availability of standard equipment (Computer lensometer, Contrasting sensitivity testing, Ultrascan, Computerized Microscopy, Fundus camera, Optical Coherence Tomography, Slit lamps) • Highly qualified & experienced clinicians • Availability of trained technicians – (Special training schools provide a steady availability of manpower) • Many technicians certified for BCVA, FP, OCT

37. Potential sites for clinical studies in India • SankaraNethralaya, Chennai • Aravind Eye Hospital, Madurai, Pondicherry & Tirunelveli • LV Prasad Eye Institute, Hyderabad • Regional Institute of Ophthalmology, Chennai • AIIMS, New Delhi • Lotus Eye Hospital, Coimbatore • Shroff Eye Hospital, Mumbai • AdityaGovt Hospital, Mumbai • Mahaveer Jain Hospital Bangalore • NarayanaNethralaya, Bangalore • Clear vision eye centre, Mumbai • Dept of Ophthalmology, Sir Ganga Ram Hospital, New Delhi • Dept of Ophthalmology, St. John’s Hospital, Bangalore • Dept of Ophthalmology, Nair hospital, Mumbai

38. Currently ongoing trials in India • Glaucoma (5) • Macular edema (2) • Refractory error (2) • Cataract (1) • Macular degeneration (1) • Eye infections * Based on current CT registry, India India participant in major global phase III trials

39. Ecron Acunova Experience in Ophthalmic studies Trials completed within planned timelines

40. Clinical research infrastructure • Availability of skilled Clinical Research Organizations including full service capabilities • Trained & experienced manpower : • Educational background – Medical, Paramedical, Life Sciences (graduate, postgraduate & Ph.D) • Experience ranging from 2-10 years • Range of services offered include: • Medical writing & Biostatistics • Clinical monitoring & Project Management • Data Management & Biometrics • Clinical supplies management • Central Laboratories • Archival facilities

41. Key enrollment indicators • Average time to reach critical milestones from contract sign off (Based on a phase III study completed at EA): • 100% sites initiated : 3.5 months • First patient enrolled : 4 months • Last patient enrolled : 6 months (Recruitment period : Actual/Planned – 8 weeks /12 weeks) • All ophthalmology studies at EA completed enrollment within planned timelines

42. Cost assumptions • Competitive service costs • Major variable cost – site cost

43. Summary and Conclusions • Indian ophthalmology industry is showing significant promise • In the coming years, the ophthalmology market will continue to support a healthy mix of both device and pharmaceutical therapies, as well as combination products that blur the line between the two industries. • More than 15000 trained ophthalmologists • Large pool of qualified, experienced, English speaking investigators and support staff • Language used for regulatory submissions & clinical research is English • Data generated in Global CTs can be used for Indian NDAs provided sufficient no. of subjects from India is included in the study • New device guidelines is expected to pave way for a significant increase in CT and device market share