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Ophthalmology Clinical Research:

The India Advantage

Points of discussion

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SN Contents

1 Ophthalmic market in India

2 Ophthalmic diseases – clinical scenario in India1. Corneal transplantation2. DME3. Glaucoma4. Refractive errors5. ARMD6. Cataract7. Uveitis8. Human resource needs

3 The Indian clinical trial space:1. Regulatory/Ethics Committee2. Institutional infrastructure3. Ongoing trials in India4. Clinical Research Infrastructure5. Key Enrollment Indicators6. Cost assumptions

4 Summary & conclusions

Ophthalmic market

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The market in India

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

4http://www.modernmedicare.in/article/Evolving-Ophthalmology/page1.html

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.

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• 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.

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Ophthalmic Device Market: India

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,

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Ophthalmic Diseases

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Clinical Scenario in India

Corneal transplantation in India

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: Potential centers in India*

Centre No of Corneal transplantation /year

L V Prasad Eye Institute Hyderabad >600

Shankara Nethralya Chennai >500

RP Centre of Ophthalmic Sciences New Delhi >400

Clear Vision Mumbai > 70

*Based on telephonic discussion with potential investigators

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

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• 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

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DME Prevalence Estimates for 2009

Population of India1 (1,197M)

Diabetic patients2: 36.4M

CSME (Based on Study 1)

• 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)

2.18M (6% of diabetic patients)

CSME (Based on Study 4)

• 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%

1.41M (3.9% of diabetic patients)

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

*Considering the fact that the mean age of patients with DME has usually been > 50 years in many studies

Worksheet Worksheet

Prevalence – DME/CSME (1/2)

Author RegionPatient segment

& nYear Prevalence in population

Sunil Gupta and Ajay Ambade1

Sunil’s Diabetes Care n’ Research Centre Pvt. Ltd. (DCRC) Nagpur

Type 2 diabetic patients (n=350)

2004

CSME: • 6% of type 2 diabetic patients• 17.9% of DR patients (type 2 diabetes)• 21.5% of insulin dependent type 2

diabetic patients• 12.96% of type 2 diabetic patients on

oral anti-diabetic drugs• 14.3% of type 2 diabetic patients with

albuminuria

Ramachandran A et al2

Diabetes Research Centre, Chennai

Type 1 diabetic patients aged < or =20 years at diagnosis of diabetes (n=617)

2000

CMSE:• 1.8% of type 1 diabetic patients aged

< or = 20 years• 13.3% of DR patients (type 1 diabetic

patients aged < or = 20 years)

V Narendran et al3

Aravind Medical Research Foundation, Aravind Eye Care System, Madurai, Tamilnadu (Study done in Palakkad, Kerala

Diabetic patients > or = 50 years (n=260)

2002

CMSE• 7.7% of diabetic patients (> or = 50

years)• 29.4% of DR patients (> or = 50

years)

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

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DME – Treatment Flow (PMR, India)

Source: KOL interviews

Diabetic Macular Edema (DME) – 100%

Clinically Significant Macular Edema (CSME) - 40%

Clinically Insignificant Macular Edema – 60%

• Irrespective of severity, CSME patients would be administered treatment

• Sometimes, physicians may also treat clinically insignificant DME (Intravitreal anit-VEGF and laser treatment on deterioration)

First-line of therapy – 100%

Focal Macular Edema

• Focal laser treatment

Diffuse Macular Edema

• Grid laser treatment

Focal Macular Edema (FME) – 60%

Diffuse Macular Edema (DiME) – 40%

Focal CSME – 40% of FME Diffuse CSME – 40% of DiME

Second-line of therapy – 25%-30%

Focal Macular Edema

• Intravitreal steroids and anti-VEGF (AVASTIN)

• Focal laser treatment

Diffuse Macular Edema

• Intravitreal steroidsand anti-VEGF (AVASTIN)

• Grid laser treatment

Third-line of therapy – 5%

Focal Macular Edema

• Vitrectomy

Diffuse Macular Edema

• Vitrectomy

CSME Treatment

DME patients constitute 90% of the Macular Edema patientsN=2

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.

15Henson DB, Thampy R. Preventing blindness from glaucoma. BMJ. 2005; 331 Suppl 7509:120-1Chew PT, Aung T. Primary angle-closure glaucoma in Asia. Journal of Glaucoma 2001; 5 Suppl 1:S7-S8

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.

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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

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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.

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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.

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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)

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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.

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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.

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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

23Indian J Ophthalmol. 2008 Nov–Dec; 56(6): 489–494. “Current status of cataract blindness and Vision 2020: The right to sight initiative in India”

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

24Murthy GV, Gupta SK, Bachani D, Jose R, John N. Current estimates of blindness in India. Br J Ophthalmol. 2005;89:257–60

Uveitis and its Classification

• Uveitis is a potentially blinding intraocular inflammation1

• The inflammation can include iris, ciliary body, choroid, retina, optic nerve and vitreous1

• 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 UveiticBlindness” AIOC 2008 PROCEEDINGS

► Location: Iris , ciliary body & cornea

► Main Causes: Idiopathic, HLA-B27 association, Trauma, Infection

Anterior Uveitis

Uveitis2

► Location: Peripheral retina, pars plana & vitreous

► Main Causes: Idiopathic, Systemic disorders like sarcoidosis, Multiple sclerosis etc

Intermediate Uveitis

► Location: Choroid & Retina

► Main Causes: Infections, Systemic disorders

Posterior Uveitis

► Location: anterior chamber, vitreous, and retina and/or choroid

► Main Causes: Infections

Pan Uveitis

Uveitis – Treatment Flow (PMR, India)

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Treated Uveitis

Anterior Uveitis (44%)

Intermediate Uveitis (16%)

Posterior Uveitis (25%)

Pan Uveitis (15%)

Infective

Non-infective

Observation (0-2%)

TopicalSteroid (90-98%)

PeriocularSteroid (5-10%)

SystemicSteroid (20-25%)

Immunosuppressant (2-5%)

Cycloplegics (80-90%)

Antibiotic(15-20%)

N=2

Steroid (100%)

Observation (0%)

TopicalSteroid (100%)

PeriocularSteroid (10-20%)

SystemicSteroid (90-100%)

Immunosuppressant (2-5%)

Acute (95%)

Chronic (5%)

Acute (40%)

Chronic (60%)

Acute (20%)

Chronic (80%)

Acute (40%)

Chronic (60%)

Acute (50%)

Chronic (50%)

Sources: KOL interviews & Secondary estimates

Acute (40%)

Chronic (60%)

Active Uveitis Prevalence Estimates for 2009

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Prevalence of Active Uveitis, 0.37%4.4M

Anterior Uveitis0.99M

Intermediate Uveitis0.36M

Posterior Uveitis0.57M

Pan Uveitis0.34M

Indian population1,197.2M

Anterior Uveitis3.65M

Intermediate Uveitis1.35M

Posterior Uveitis2.1M

Pan Uveitis1.27M

Anterior Uveitis1.92M

Intermediate Uveitis0.71M

Posterior Uveitis1.11M

Pan Uveitis0.67M

Downside case

Upside case

Base Case

Numbers in million

Prevalence of Active Uveitis, 0.19%2.2M

Prevalence of Active Uveitis, 0.70%8.38M

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%

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%

28http://www.who.int/blindness/Vision2020%20-report.pdf

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

29http://www.aios.org/cmefiles/CME_9.pdf

Human Resource needs: India

Vision 2020: CME series 9

30There are >15000 trained ophthalmologists in India

Clinical Profile of Institutions in India

Based on survey with 128 medical institutions offering training 31

The Clinical Trial Space

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Scenario in India

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

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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)

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Regulatory Environment: General classification

CLASS RISK LEVEL DEVICE EXAMPLES

A Low Risk Thermometers / tongue depressors

B Low-moderateRisk

Hypodermic Needles / suction equipment

C Moderate-highRisk

Lung ventilator / bone fixation plate

D High Risk Heart valves /implantable defibrillator

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The Figure shows increasing levels of regulatoryrequirements as the device risk class increases

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

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Potential sites for clinical studies in India

• Sankara Nethralaya, 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

• Aditya Govt Hospital, Mumbai

• Mahaveer Jain Hospital Bangalore

• Narayana Nethralaya, 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

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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

38India participant in major global phase III trials

Ecron Acunova Experience in Ophthalmic studies

Sl No.

Indication Phase of study

Sample size(Pts)

No of sites

1 Allergic conjunctivitis III 120 6

2 Cataract III 75 6

3 Glaucoma III 120 10

4 Glaucoma III 30 5

5 Post Cataract Surgery

III 150 6

6 Cataract III 210 6

39Trials completed within planned timelines

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

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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

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Cost assumptions

• Competitive service costs

• Major variable cost – site cost

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SAMPLE INVESTIGATOR SITE COST STRUCTURE Per visit 3 VisitsPrincipal Investigator (per patient / visit) USD 60 -150 USD 180 - 450

Co-Investigator (per patient / visit) USD 40 - 80 USD 120 - 320

Per month 6 monthsStudy coordinator (monthly) USD 200 -300 USD 1200 - 1,800

Ethics committee (One time payment) USD 200 - 400

Other costs Institutional fee (20% of overall budget) Clinical & Lab investigations (based on protocol)

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

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