Ophthalmology Clinical Research:

1
Ophthalmology Clinical Research The India
Advantage
2
Points of discussion
SN Contents
1 Ophthalmic market in India
2 Ophthalmic diseases clinical scenario in India Corneal transplantation DME Glaucoma Refractive errors ARMD Cataract Uveitis Human resource needs
3 The Indian clinical trial space Regulatory/Ethics Committee Institutional infrastructure Ongoing trials in India Clinical Research Infrastructure Key Enrollment Indicators Cost assumptions
4 Summary conclusions
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-Opht
halmology/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
  Indias 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 gt10 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, JJ vision care. Appasamy Associates,
  Mehra Eyetech Pvt. Ltd., Toshbro Medicals,

8
Ophthalmic Diseases

• Clinical Scenario in India

9
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

10
Corneal transplantation Potential centers in
India
Centre No of Corneal transplantation /year
L V Prasad Eye Institute Hyderabad gt600
Shankara Nethralya Chennai gt500
RP Centre of Ophthalmic Sciences New Delhi gt400
Clear Vision Mumbai gt 70
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 101
• 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,
2Macular Edema, Diabetic, emedicine Website
Accessed on May 12, 2009, 3International
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 0.013
• Prevalence rate of CSME among diabetic patients
  (based on the above assumption) 6 (Study 1)

• Assumption the prevalence of DME in diabetic
  patients lt 30 years of age is negligible
• Adjusting the prevalence rate of CSME to all age
  group (Study 4)
• Prevalence of CSME in diabetic patients gt
  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 gt 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. 2710471053 3Pushpa
Krishna et al (2005), Dyslipidemia in Type 1
Diabetes Mellitus in the Young, International
Journal of Diabetes in Developing Countries
2005Vo1 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
2009296-11
13
Prevalence DME/CSME (1/2)
Author Region Patient segment n Year Prevalence in population
Sunil Gupta and Ajay Ambade1 Sunils Diabetes Care n Research Centre Pvt. Ltd. (DCRC) Nagpur Type 2 diabetic patients (n350) 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 lt or 20 years at diagnosis of diabetes (n617) 2000 CMSE 1.8 of type 1 diabetic patients aged lt or 20 years 13.3 of DR patients (type 1 diabetic patients aged lt or 20 years)
V Narendran et al3 Aravind Medical Research Foundation, Aravind Eye Care System, Madurai, Tamilnadu (Study done in Palakkad, Kerala Diabetic patients gt or 50 years (n260) 2002 CMSE 7.7 of diabetic patients (gt or 50 years) 29.4 of DR patients (gt 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. 2475-78,
2Ramachandran A et al (2000), Vascular
Complications in Young Asian Indian Patients with
Type 1 Diabetes Mellitus, Diabetes Res Clin
Pract. 2000 Apr48(1)51-6, 3V Narendran et al
(2002), Diabetic retinopathy among self reported
diabetics in southern India a population based
assessment, Br J Ophthalmol 20028610141018
14
DME Treatment Flow (PMR, India)
N2
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 (Intravitreal anit-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
• Intravitreal steroidsand 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 worlds 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 7509120-1 Chew
PT, Aung T. Primary angle-closure glaucoma in
Asia. Journal of Glaucoma 2001 5 Suppl 1S7-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
• NdYAG 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 lt 6/18 in
  the better eye, excluding presbyopia.
• Globally, uncorrected refractive errors are the
  main cause of visual impairment in children aged
  515 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 patients
  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
  worlds 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 NovDec 56(6)
489494. 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. 20058925760
25
Uveitis and its Classification

• Uveitis is a potentially blinding intraocular
  inflammation1
• The inflammation can include iris, ciliary body,
  choroid, retina, optic nerve and vitreous1

Uveitis2
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 Delhi3
• 65 no definitive etiology
• Systemic disorders Ankylosing spondilytis, TB,
  juvenile idiopathic arthritis and sarcoidosis
• Ocular disease Ocular toxoplasmosis
• Other Serpiogenous chorditis, Behcets 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
N2
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/Vision202020-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 gt15000 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
CLASS RISK LEVEL DEVICE EXAMPLES
A Low Risk Thermometers / tongue depressors
B Low-moderate Risk Hypodermic Needles / suction equipment
C Moderate-high Risk Lung ventilator / bone fixation plate
D High Risk Heart valves /implantable defibrillator
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

• 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. Johns 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
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
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

SAMPLE INVESTIGATOR SITE COST STRUCTURE SAMPLE INVESTIGATOR SITE COST STRUCTURE SAMPLE INVESTIGATOR SITE COST STRUCTURE
  Per visit 3 Visits
Principal Investigator (per patient / visit) USD 60 -150 USD 180 - 450
Co-Investigator (per patient / visit) USD 40 - 80 USD 120 - 320
  Per month 6 months
Study 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)    
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