clinical translation of neuro-regenerative …...underlying causes of dysfunction and disease [3]....

CLINICAL TRANSLATION OF NEURO-REGENERATIVE MEDICINE IN INDIA

A study on barriers and strategies

by

Mark Joseph Messih

A thesis submitted in conformity with the requirements for the degree of Master of Science

Institute of Medical Sciences University of Toronto

© Copyright by Mark Messih (2010)

ii

CLINICAL TRANSLATION OF NEURO-REGENERATIVE

MEDICINE IN INDIA

A study on barriers and strategies

Mark Messih

Masters of Science

Institute of Medical Sciences University of Toronto

2010

Abstract

The prevalence of neurodegenerative disease in India is rising. Regenerative medicine (RM) is

being developed to treat these conditions. However, despite advances in RM application for

neurological disorders (NeuroRM), there is a lack of research on clinical translation of NeuroRM

technologies in developing countries. Given that India is one of the first nations to translate in

this field, much can be learned on challenges and solutions arising during translation. This study

identifies stakeholders involved in such translation and outlines roles of each; it describes India’s

regulatory environment concerning NeuroRM translation; and discusses the impact of

collaboration in clinical translation. Twenty-three face-to-face interviews with clinicians,

researchers and policy-makers within India were undertaken and transcripts subjected to thematic

analysis. The study demonstrates that clinical translation of NeuroRM within India is taking

place robustly, it identifies barriers and good practices being adopted, and provides

recommendations based on participants’ experiences.

iii

Table of Contents

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vi

List of Tables

Table 1-1 Etiology of neurodegenerative disease ........................................................................... 5!

Table 1-2 Symptoms of neurodegenerative disease ........................................................................ 5!

Table 1-3 Population of India aged 60+ ......................................................................................... 6!

Table 1-4 Global prevalence of neurodegenerative disease 2005-2030 ......................................... 8!

Table 1-5 Epidemiology of neurodegenerative disease within India 1987-2004 ........................... 8!

Table 1-6 NeuroRM targets and approaches ................................................................................ 12!

Table 1-7 Indian Neuroscience Research Centres ........................................................................ 13!

Table 1-8 Applications of Regenerative Medicine in Developing Countries ............................... 14!

Table 1-9 Indian Stem Cell Research Centres .............................................................................. 15!

Table 1-10 Conditions and NeuroRM studies within India .......................................................... 16!

Table 2-1 Institutions Visited (April – May, 2009) ...................................................................... 24!

Table 3-1 Funding sources ............................................................................................................ 45!

Table 3-2 AIIMS Stem Cell Facility Projects ............................................................................... 46!

vii

List of Figures

Figure 1 Disability Adjusted Life Years (DALY) for neurological disorders ................................ 7!

Figure 2 Map of Data Collection Sites ......................................................................................... 25!

Figure 3 Relinethra Epithelial Graft Kit ....................................................................................... 39!

viii

List of Appendices

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1

Chapter 1 Introduction Morbidity and mortality due to chronic non-communicable diseases including cardiovascular

disease, diabetes [1] and neurodegenerative diseases is rising [2]. Researchers and clinicians are

searching for novel treatments that not only target the symptoms of these conditions but the

underlying causes of dysfunction and disease [3]. Regenerative medicine (RM) has the potential

to improve the health of people living in developed and developing countries [4,5]. Currently,

there is ongoing debate surrounding clinical application of regenerative medicine technologies

for treatment of neurodegenerative disease (NeuroRM) [6,7]. Discussion centres on whether

these interventions have been sufficiently studied to warrant clinical application. While research

on NeuroRM translation has focused on developed nations [8], studies in developing countries

have not been undertaken. Given that India is one of the first nations to translate in this field,

much can be learned about challenges and solutions arising during translation. This study

entitled “Clinical Translation of Neuroregenerative Medicine in India” asks, what are the

challenges to translation of NeuroRM within India and how are these being addressed? To

address this, the study will meet the following three objectives:

1. Identify the stakeholders involved in translation, including the roles and challenges faced

by each in clinical translation.

2. Describe India’s regulatory environment concerning NeuroRM translation by

determining which agencies are involved and their role in clinical translation.

3. Determine the role of collaboration in clinical translation by mapping where

collaborations develop and how partnerships impact translation.

2

Rationale for Objective selection

Objective 1: Existing literature on translation [9] indicates that this process involves different

stakeholders including scientists and physicians. In order to identify the barriers and strategies to

translation, determining who the relevant parties are is critical. By mapping where translation

takes place, this study has identified challenges to translation in each stage of this process.

Objective 2: Regulations greatly impact how translation takes place within a nation. Sabroe et al

(2007) have identified how government priorities impact funding and oversight for translational

research [10]. Khoury et al (2008) [11] discuss the important role government agencies have in

setting standards for ethical conduct of research and clinical practices. This study will identify

which agencies are involved in NeuroRM translation, impacts on translation and the experiences

of clinicians and researchers working within this system. By meeting this objective, this research

identifies barriers and strengths in government activity.

Objective 3:Literature on clinical translation has shown that collaboration is important in

fostering clinical development of basic research discoveries. As put forward by Litman et al

(2007) [12]

Biomedical research function[s]as a substrate for the catalytic activity of translational

research… The secret to this catalytic reaction rests in the ability to integrate disciplines

of increasing complexity by allowing a dialogue among the stakeholders, by identifying

the hurdles that hamper this interaction and propose creative solutions.

Through the exploration of these three objectives, translation of NeuroRM in India is

documented from preclinical research into clinical trials and commercial products. Identifying

the stakeholders and observing collaborations between groups has identified barriers to

translation based on the experiences of interviews. Determining government involvement in

translation provides context in which this phenomenon takes place and allows this work to

identify policies that foster or hinder translation.

To meet these objectives, a qualitative case study has been undertaken in which twenty-three

interviews were conducted in India over two weeks from April – May 2009. This was

supplemented by a review of primary and secondary documents and notes taken during each

3

interview. Chapter 2 reviews the methodology employed, presenting relevant qualitative research

theory and outlines how data was collected and analyzed in this work. Chapter 3 presents the

results of this study. First, stakeholders involved in translation are identified and their

involvement in translation is reviewed. Next, the Indian government’s involvement in

translation is shown to fall into three categories 1) Funding 2) Regulation and 3) Collaboration

Development. In closing, data on collaboration in translation is outlined. Categories of

partnerships are identified and outcomes of these agreements stated. Chapter 4 discusses the

implications of the findings as they relate to the overarching question of this work: “What are the

challenges and strategies translation of NeuroRM within India?” The chapter is structured around

the three objectives identified above.

Next, I will define terms and concepts applied in this research and discuss literature that has

informed this study from the following areas:

• Epidemiology of Neurodegenerative disease (1.3)

• Regenerative Medicine (1.4)

• Translational Research (1.5)

• Neuroscience innovation within India (1.6)

I will then discuss the gap in knowledge addressed by this work and detail why it is important to

address this gap.

1.1 Definition of Key Concepts and Terms

Neurodegenerative diseases affect the central nervous system (brain, spinal cord) and

peripheral nervous system [13]. These conditions are characterized by progressive loss of

neurons and synapses in selective areas of the nervous system.

Neuro-Regenerative Medicine (NeuroRM) refers to the application of regenerative medicine

approaches, such as stem cell technologies, tissue engineering and gene therapy, within the

nervous system in order to slow or reverse the deterioration associated with deeply debilitating

neurodegenerative disorders [14].

4

Basic Research refers to the laboratory studies that provide the foundation for clinical research

[15]. Basic research centres on the acquisition of knowledge without the obligation to apply it to

practical ends [16].

Clinical Research, as defined by the National Institutes of Health Director’s Panel on Clinical

Research [17], refers to the following:

1. Patient-oriented research including research with human subjects, or material of human

origin such as tissue

2. Epidemiological and behavioural studies

3. Outcomes research and health services research

Translational research, as defined by the National Institutes of Health, includes two areas of

translation. The first (T1) is the application of research discoveries from the laboratory, and

preclinical studies, in human studies and therapy. The second (T2) concerns adoption of new

knowledge in clinical practice and health policy development [18].

In the next section, background literature is presented provide the reader with a context for this

research. First, the burden of neurodegenerative diseases, both within India and globally, is

outlined to highlight the current impact of these conditions. Current treatment options for

neurodegeneration and shortcomings of these approaches are discussed to convey the need for

innovative solutions, such as NeuroRM, to neurodegeneration. Subsequently, literature on

regenerative medicine, specifically neuroregenerative medicine, is reviewed. Finally, the chapter

discusses NeuroRM innovation within India to identify the strategies that have emerged for

addressing challenges in NeuroRM translation. This section explores the existing regulatory,

research and clinical infrastructure in place that is supporting NeuroRM development.

1.2 Burden of Neurodegenerative disease

The burden of neurodegenerative disease is discussed here to evaluate the need for innovative

solutions for neurodegenerative diseases. This section identifies conditions targeted by NeuroRM

interventions and demonstrates the need for new approaches. First the morbidity due to these

disorders is stated. Next the global epidemiology of neurodegenerative disease is outlined

followed by data on neurodegenerative disease epidemiology in India.

5

1.2.1 Etiology of Neurodegenerative Disease

Neurodegenerative diseases affect the central nervous system (brain, spinal cord) and peripheral

nervous system [19]. They can cause progressive cognitive, sensory and/or motor dysfunction

[20] and are caused by several mechanisms (see table 1.1)

Table 1-1 Etiology of neurodegenerative disease

Protein misfolding and/or defective degradation

Disruption of cellular/axonal transport

Oxidative stress and formation of free radicals

Actions and mutations of molecular chaperones

Mitochondrial dysfunctions Dysfunction of neurotrophins Fragmentation of neuronal Golgi apparatus Neuro-immune processes

Source: Bernal GM, Peterson DA. Neural stem cells as therapeutic agents for age-related brain repair. Aging Cell. 2004

Dec; 3(6): 345-351.

According to the National Institutes of Neurological Disorders (NINDS), neurodegenerative

disorders impact patient movement, cognition and behaviour (see table 1.2)

Table 1-2 Symptoms of neurodegenerative disease

Movement Cognition Strength PNS/ANS* Coordination Myelin Loss

Parkinson’s disease

Alzheimer’s disease

Amyotrophic lateral sclerosis

Amyloidoses

Spinocerebellar atrophies

Multiple Sclerosis

Fronto-temporal dementia



Toxin related

Friedreich’s ataxia

Charcot Marie Tooth

Dementia with Lewy bodies

Dementia with Lewy bodies

Hereditary spastic paraparesis

Metabolic (diabetes) related

Prion disorders

Corticobasal degeneration

Corticobasal degeneration

Spinocerebellar atrophies


Progressive supranuclear palsy

Progressive supranuclear palsy


Multiple system atrophy

Prion disorders

Prion disorders

Huntington’s disease

Source: Forman MS, Trojanowski JQ, Lee VM-. Neurodegenerative diseases: a decade of discoveries paves the way

for therapeutic breakthroughs. Nat.Med. 2004 print; 10(10): 1055-1063

6

1.2.2 Epidemiology of Neurodegenerative Disease

1.2.2.1 Aging and Neurodegeneration

The World Health Organization estimates that 737 million persons worldwide are estimated to be

60 years of age and older in 2009 [21]. This is projected to increase to 2 billion in 2050. Within

India by 2050, 227,032,000 additional persons will be aged 60 and older (see table 1.3). As a

percentage of the total population, this translates to one in nine persons in 2009 and one in five

persons by 2050.

Table 1-3 Population of India aged 60+

Number of individuals aged

60 and older

Percentage of total

population

Percentage of 60+

individuals over the

age of 80

Life expectancy at

age 60 2005-2010

2009 2050 2009 2050 2009 2050 Men Women

88,605,000 315,637,000 7 20 9 13 16 18

Source: World Health Organization: Department of Economic and Social Affairs - Population Division. Population

Aging and Development 2009. 2009; Available at: http: //www.un.org/esa/population/publications/ageing/ageing2009.htm.

Accessed 06/30/2010.

Life expectancy at age 60 refers to the number of years a person will live after reaching 60. The

number of persons aged 80 and older is also projected to increase. The percentage share of

persons 80 years of age or older identifies the percentage of 60+ individuals, over the age of 80.

Ageing affects many cellular processes that predispose patients to neurodegeneration [22-24].

Given the correlation between aging and neurodegenerative disease, it can be predicted that the

prevalence and incidence of these disorders will rise. This suggests that aging related disorders

will become increasingly prevalent within India.

1.2.2.2 Prevalence of Neurodegenerative Disease

The impact of neurological disorders has been measured by Disability Adjusted Life Years

(DALYs) [25] by the World Health Organization, Report on Neurological Disorders. The DALY

is calculated by determining the number of years of life lost to premature mortality (YLL) and

years living with disability (YLD). Figure 2.1 indicates that the burden of neurological disorders

is already greater than other chronic non-communicable diseases and infectious disease.

7

Neurological disorders in this reported include dementia, epilepsy, headache disorders, multiple

sclerosis, neuroinfections, Parkinson’s disease, stroke and traumatic brain injuries. Furthermore,

neurodegenerative diseases commonly impact elderly populations over a long period of time

suggesting that the high DALY is due to the higher number of years living with disability

(YLD). This indicates that there is a large population living with neurodegenerative disease, that

these disorders are causing high levels of morbidity in the elderly and, finally, underscores the

importance of developing treatments for neurological diseases in both developing and developed

nations.

Figure 1 Disability Adjusted Life Years (DALY) for neurological disorders

Source: World Health Organization. Neurological disorders: public health challenges. Geneva: World Health

Organization; 2006.

Table 1.4 outlines the prevalence of neurodegenerative disorders per 1000 individuals according

to the WHO study on the burden of Neurological disorders. Data from 2005 and projected

statistics for 2030 are enumerated below. Percentage changes over time are added to show the

rising prevalence of conditions including Alzheimer’s, multiple sclerosis and neurological

injuries. Note the large predicted increases in neurological injuries, dementia and Parkinsonism.

Conversely, infections and nutrition related neurodegeneration would fall by 2030. This indicates

that future neurodegenerative diseases will be predominantly caused by age related degeneration

and injury.

8

Table 1-4 Global prevalence of neurodegenerative disease 2005-2030

Disorder 2005 2030 Percentage change Epilepsy 6.19 6.3 1.78 Alzheimer’s and other dementias 3.79 5.56 46.7 Parkinson’s Disease 0.81 0.91 12.3 Multiple sclerosis 0.39 0.41 5.13 Migraine 50.64 52.15 2.98 Cerebrovascular disease 9.55 9.7 1.57 Neuroinfections 2.82 1.68 -40.4 Nutritional and neuropathies 54.72 36.04 -34.1 Neurological injuries 26.45 30.66 15.91 Total 155.36 143.5 -7.63

Source: World Health Organization. Neurological disorders: public health challenges. Geneva: World Health

Organization; 2006.

1.2.2.3 Epidemiology of Neurodegenerative disease in India

The prevalence of neurological disorders is rising in India [26]. Table 1.5 presents data from six

epidemiological studies conducted between 1987 and 2004. According to these studies, the

prevalence of Parkinsonism, peripheral neuropathies and stroke is rising within India. These

findings outline the prevalence per 1,000 of conditions listed below. If these numbers are

extrapolated to India’s current population of 1,173,108,018 [27], this translates into 1,759,662

stroke patients, 1,501,578 peripheral neuropathy patients and 387,125 Parkinson’s patients.

Table 1-5 Epidemiology of neurodegenerative disease within India 1987-2004

Disorder Gouri-Devi Bharucha Kapoor Razdan Das Gouri-Devi

1987 1987 1989 1994 1996 2994

Epilepsy 4.63 4.7 4.02 2.47 3.05 8.83

Headache 1.73 N/A 16.95 N/A 18.58 11.19

Stroke 0.52 17.6 0.88 1.43 1.26 1.50

Mental Retardation and Cerebral Palsy 1.63 2.4 1.09 3.3 0.64 1.42

Parkinson’s disease 0.07 7.1 N/A 1.4 0.16 0.33

Peripheral Neuropathy 0.52 015.2 N/A 2.99 0.74 1.28

Post poliomyelitis 0.92 N/A 4.95 2.18 0.55 1.1

Source: Gourie-Devi M. Organization of neurology services in India: Unmet needs and the way forward. Neurol.India

2008 /1/1; 56(1): 4-12.

9

The section above outlined the burden of neurodegenerative disease globally and within India. In

the next section, the process of applying new interventions for treating disease, clinical

translation, is defined and existing methods for challenges in translation are reviewed.

1.3 Translational Research

Translational research refers to the application of research discoveries from the laboratory in

human studies. Researchers have identified two “Translational Blocks” [29] that hinder

translation of basic research into therapy. The first is the “basic science to human studies” block,

(T1). The second is “Translation of new knowledge into clinical practice and health decision-

making”, (T2) block. T1 barriers arise when taking new discoveries from basic research into

clinical trials. T2 barriers prevent acceptance of new therapies in standard practice. This study

focuses on T1 barriers. Given the novelty of NeuroRM and lack of consensus on its application

globally, we are not yet at the stage to focus on the second barrier. As put forward by Littman et

al (2007)[30], in order to address these blocks, “translational researchers need to identify

scientific, financial, ethical, regulatory, legislative and operational hurdles and provide creative

solutions to facilitate this process.” The next section presents examples of organizations that

have identified translational blocks and their methodology.

1.3.1 Identifying Barriers to Translation

To learn how to study potential T1 barriers to translation of NeuroRM, I reviewed previously

published policies on translational research that identified bottlenecks in this process. Identifying

barriers has taken place in two stages. First, a multidisciplinary panel composed of clinicians,

researchers and policy makers is assembled. The National Institutes of Health Roadmap for

Medical Research received extensive input from researchers, officials and clinicians [31] in

developing good clinical research policy. The International Society for Stem Cell Research

(ISSCR) [32] assembled a taskforce of clinicians and researchers to draft the Guidelines for the

Clinical Translation of Stem Cells. Then these panels discussed barriers to translation including

scientific, financial and ethical considerations. While the ISSCR has published international

guidelines on stem cell translation, recommendations may require reconciliation with country-

specific regulations as reflected in the following excerpt from the ISSCR Guidelines for the

Clinical Translation of Stem Cells:

10

The ISSCR recognizes the value of having separate jurisdictions provide their own regulations covering medical innovations using stem cells or their direct derivatives and strongly recommends the creation of such regulations through consultation with expert scientists, clinicians, and ethicists. Clinician-scientists and their institutions have a duty to follow local regulations or laws, whenever they exist.

This study has been informed by these examples by engaging a range of stakeholders working in

research, clinical settings and government to determine barriers to translation. Through this

approach, we can observe the realities of clinical translation on the ground in India by obtaining

first hand information from stakeholders. Translational research of neuroscience technologies is

discussed next.

1.3.2 Translational Research in Neuroscience

Translational neuroscience research centres on the movement of knowledge from basic research

on central nervous system structure and function to generate pharmacological, surgical, and

behavioral therapies [33]. Recurring barriers, according to the Center for Translational

Neuroscience at Duke University, include regulatory and financial considerations [34]. While

funding is available for preclinical research, scientists reported limited support for initiation of

clinical trials [35]. In response to these concerns, government agencies are revising policies to

support preclinical research that is linked to clinical outputs [36]. For example, The United States

National Institutes of Health, National Institutes of Neurological Disorders and Stroke (NINDS)

increased funding allocated for translational research and therapy development [37]. To date, no

translational neuroscience research on neuroregenerative technologies has been conducted. The

case of a Geron Corp is presented as an example of the challenges in translating NeuroRM

research into clinical study and compared to reports of embryonic stem cell use from Nu-Tech

Mediworld, a small firm that currently offers embryonic stem cells marketed as therapy.

Geron became the first U.S firm to obtain Food and Drug Administration (FDA) approval to

conduct trials using human embryonic stem cells for spinal cord injury in January 2009. The

process for obtaining approval included construction of new research facilities and submission of

a 22,000-plus pages Investigational New Drug application [38]. In comparison, Indian firm Nu-

tech Mediworld has commercialized embryonic stem cell products for a range of conditions

including spinal cord injury and stroke. This firm has not disclosed the methods employed and

no publications on the efficacy of offered treatments have come out of the centre to date [39].

11

These two firms are outlined here to contrast the experiences of firms in different nations. This

comparison suggests that standard protocols for conducting NeuroRM trials and commercializing

are needed to move forward with NeuroRM translation.

Having identified the burden of neurodegenerative disease and background on the process of

clinical translation, I next present literature on one field of interest in this study, Neuro-

regenerative medicine. Neuro-regenerative medicine is compared with existing treatments for

neurodegeneration to highlight the importance of translating regenerative technologies. This is

discussed to suggest that RM offers potential health solutions that are not currently available.

1.4 Regenerative Medicine

1.4.1 Advantages of Regenerative Medicine Over Current Treatment

Current treatments for neurodegenerative disease focus on managing symptoms without targeting

the underlying cause of degeneration [40, 41]. Examples include dopamine-blocking

medications to treat chorea due to Huntington’s disease and dopamine replacement therapy in

Parkinson’s patients. These technologies may be inaccessible to patients as drug treatments must

often be taken for years at a time. Dementia currently costs the Government of India

$3,366,300,000 (CAN) and Parkinson’s patients currently spend 16% to 41.7% of annual income

on current medication (Rekha J et al, 2002) [41]. Regenerative Medicine (RM) differs from such

traditional interventions by targeting the underlying dysfunction [42] of neurodegenerative

disease by replacing cells and tissues. While the final cost of potential therapy has not been set,

regenerative medicine interventions will involve fewer treatments and have lasting impact in

comparison to current therapies.

1.4.2 Defining Regenerative Medicine

Regenerative medicine is [43]:

An interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause, including congenital defects, disease, trauma and ageing. It uses a combination of several converging technological approaches, both existing and newly emerging, that moves it beyond traditional transplantation and replacement therapies. These approaches may include, but are not limited to, the use of soluble molecules, gene therapy, stem and progenitor cell therapy, tissue engineering and the reprogramming of cell and tissue types.

12

This definition informed how conditions of interest were selected, technologies explored and

relevant stakeholders identified in this study. Conditions of interest are neuro-degenerative

diseases precipitated by causes including disease, trauma and/or aging. Given the

interdisciplinary nature of RM, stakeholders with expertise in different fields such as genetics,

cell biology and tissue engineering were engaged.

1.4.3 Neuro-Regenerative Medicine (NeuroRM)

NeuroRM refers to the application of RM interventions to replace and repair-damaged cells in

the central nervous system (CNS) in order to restore lost or damaged neural tissue [44].

NeuroRM strategies include the use of scaffolds, stem cells, gene therapy and growth factors for

treatment of neurodegenerative diseases such as Alzheimer’s, Huntington’s and Spinal Cord

Injury. I have generated a table (see table 1.6), which provides examples of neurodegenerative

conditions targeted and technologies applied.

Table 1-6 NeuroRM targets and approaches

Condition Approach Author Alzheimer’s Transgenic stem cell implantation Sugaya et al (2006) [45] Amyotrophic Lateral Sclerosis

Adeno-associated viral (AAV) vectors

Federici et al (2010) [46]

Corneal Degeneration Electrospun scaffolds Deshpande et al (2010) [47] Huntington’s Disease DNA vaccines Nie et al (2007) [48] Neural Trauma Microencapsulated choroid plexus

epithelial cell transplants Thanos et al (2010) [49]

Parkinsonism Gene therapy Date et al (2009) [50] Peripheral Neuropathies Neurotransmitters, neuroactive

steroids, and neurohormones Magnaghi et al (2009) [51]

Spinal Cord Injury Bone marrow stromal cells Vaquero et al (2009) [52] Stroke Neurosprothetic devices Leach et al (2010) [53] Traumatic Brain Injury Vascular endothelial growth

factor Lee et al (2010) [54]

Multiple Targets Hydrogel scaffolds for repair factor delivery

Katz et al (2009) [55]

Induced pluripotent stem cells Koch et al (2009) [56] Mesenchymal stem cells for Neural Repair

Miller et al (2010) [57]

Nanotechnologies Kubinova et al (2010) [58] Nanoparticles Wang et al (2010) [59] Viral vector-mediate gene transfer of neurotrophic factors

Lim et al (2010) [60]

13

The previous sections have identified the burden of neurodegeneration within India and

described what NeuroRM is and how it differs from existing treatments. The next sections

highlight the state of neuroscience research and NeuroRM within India.

1.4.3.1 Mapping Neuroscience Institutions

A bibliometric analysis of Indian research centres [61] has identified hubs of neuroscience

activity within the country. Data on total publications (TP), total citations (TC) and average

citation per paper (ACPP) research output from leading institutions are included in Table 1.7.

Table 1-7 Indian Neuroscience Research Centres

Name of Institution TP TC ACPP All India Institute of Medical Sciences, Delhi 490 925 1.89 National Institute of Mental Health and Neurosciences, Bangalore 262 737 2.81 Post Graduate Institute of Medical Education and Research, Chandigarth

210 260 1.24

Indian Institute of Science, Bangalore 195 870 4.46 Christian Medical College, Vellore 171 294 1.72 Sanjay Gandhi Postgraduate Institute of Medical Sciences, Luck now 156 365 2.34 Sree Chitra Tirunal Institute of Medical Sciences, Chandigarh 125 257 2.06 King Edward Memorial Hospital, Mumbai 104 96 0.92 University Institute of Pharmaceutical Sciences, Chandigarh 70 447 6.39 Indian Institute of Chemical Biology, Kolkata 65 268 4.12 L.V. Prasad Eye Institute, Hyderabad 61 90 1.48 University of Madras, Chennai 61 216 3.54 National Brain Research Center, Manesar 60 259 4.32 Nizam’s Institute of Medical Sciences, Hyderabad 60 63 1.05

Source: Bala A, Gupta B. Mapping of Indian neuroscience research: A scientometric analysis of research output during

1999-2008. Neurology India 2010 January 1/2010; 58(1): 35-41.

This table demonstrates that neuroscience research is taking place throughout India. This data

has informed what centres were contacted and indicates India is investing in developing its

neuroscience research infrastructure. Currently, there is no literature that identifies neuroscience

institutions, specifically on neuroregenerative research within India. This presents a potential gap

that is addressed by this research.

14

1.4.3.2 Rational for Selecting India for this research

Governments in emerging economies are allocating significant resources for research and

development of regenerative medicine technologies that can address local health needs (Lander

et al, 2008 [62]). Lander’s research, (see table 1.8) presents targets of RM treatments including

neurodegenerative conditions such as peripheral nerve injuries and spinal cord injuries.

Table 1-8 Applications of Regenerative Medicine in Developing Countries

Source: Lander B, Thorsteinsdottir H, Singer PA, Daar AS. Harnessing stem cells for health needs in India. Cell Stem

Cell 2008 Jul 3; 3(1): 11-5.

15

Previous research has shown that India is developing its stem cell sector through generation of

guidelines, funding, and development of new research institutions. I have compiled a list of

Indian institutions conducting stem cell research (see table 1.9) regenerative medicine

technologies to treat a range lists Indian stem cell research institutions and categories of stem

cells used [63]. This table demonstrates India’s investment in stem cell research and was

important in identifying centres of interest in this study.

Table 1-9 Indian Stem Cell Research Centres

Research Centre ESC HSC LSC NSC MSC CBB All India Institute of Medical Sciences ! ! Centre for Human Genetics ! Christian Medical College ! ! Indian Institute of Sciences ! Indian Institute of Technology ! L.V. Prasad Eye Institute ! Manipal Hospital ! ! National Brain Research Centre ! ! National Centre for Biological Sciences ! ! National Centre for Cell Sciences ! ! ! ! National Centre for Immunology National Institute for Research in Reproductive Health !

National Institute of Mental Health and Neurosciences !

Post Grad. Inst. of Medical Education & Research !

Rajiv Gandhi Centre for Biotechnology ! Regional Institute of Ophthalmology ! Research and Referral Hospital ! Sanjay Gandhi Post Graduate Institute of Medical Sciences

! !

University of Hyderabad ! Reliance Life Sciences ! Life Cell !

Source: Tandon PN. Transplantation and stem cell research in neurosciences: where does India stand? Neurol.India

2009 Nov-Dec; 57(6): 706-714.

Note: ESC-Embryonic, HSC-Hematopoietic, LSC-Limbal, NSC-Neural, MSC-Mesenchymal, CBB-Cord Blood Bank

Researchers are studying RM approaches including the use of artificial organs, molecular

scaffolds and tissue-engineered cells. I have generated a table of recent publications in NeuroRM

from Indian scientists to reflect the range of conditions targeted and strategies employed (see

table 1.10). In 2007, the Society for Tissue Engineering and Regenerative Medicine (India) was

launched to promote national development of basic and clinically oriented research of tissue

16

engineering and regenerative medicine [64].

Table 1-10 Conditions and NeuroRM studies within India

Condition Intervention Author Alzheimer’s disease Hepatocyte Growth Factor Sharma (2010) [65] Corneal Degeneration Corneal limbal epithelial cells

on scaffold polymers Sitalakshmi et al (2008) [66]

Multiple Sclerosis Myelin Nanodelivery Dharamkar et al (2008) [67] Parkinson’s Disease Bone marrow derived

Mesenchymal stem cells Venkataraman (2010) [68]

Spinal Cord Injury Bone Marrow Cells and Neurotransmitters

Paulose (2009) [69]

Multiple Targets

Neural Progenitor cells Srivastava et al (2009) [70] Mesenchymal Stem Cells Satija (2009) [71] Biomaterial scaffolding Subramanian (2009) [72]

This tells us that NeuroRM research and clinical application is rising within India. When

combined with the epidemiological trends outlined in Section 1.2, it can be inferred that

translational activity will rise.

1.5 Gap in the Literature

Having reviewed the literature in the fields of neuro-regenerative medicine, clinical translation

and neuroscience innovation in India, the following gap has been identified and will be

addressed in this study:

Neurodegenerative disease conditions have debilitating and long-term impacts in elderly

populations within India and globally. While existing treatments for neurodegenerative disease

are available, these target symptoms of neurodegeneration. Current therapies are expensive and

require years of use. This has created a demand for treatments that are less expensive in the long

term. Regenerative medicine has been shown, in previous studies, to be one option for treating

underlying causes of degeneration. Furthermore, studies have shown India is translating

regenerative medicine technologies to address local health needs. What has not been studied, to

date, is the translation of RM technologies to address neurodegenerative diseases.

Looking at literature on translational research, scholars emphasize the importance of identifying

challenges and solutions in translation through discussions with scientists, ethicists, clinicians

and policy-makers. While past research has studied the field of regenerative medicine in India, I

17

put forward that focusing on neurodegenerative disease allows us to better discern challenges in

barriers by specifically focusing on relevant stakeholders working in this field.

This study is the first to centre on the application of RM to treat neurological disorders. India

was selected for this research as it is one of the few nations in which translation of NeuroRM is

taking place currently. As this research will present in Chapter 3, clinical trials and commercial

products are emerging for neurodegenerative diseases. Furthermore, government funding and

infrastructure development for this field is rising within India. This study will focus specifically

on the identification of challenges arising during translation, in India, and strategies applied by

stakeholders to overcome these.

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Chapter 2 Method

2.1 Introduction

In this chapter, the case study methodology used in this work will be discussed as is the rationale

for applying this method and limitations of this approach. Next, I will outline participant

selection criteria and recruitment strategies. Twenty-three interviews were undertaken in this

study. A member check was performed in which participants were contacted by email with a

statement of the objectives of this study and a summary of the findings of this work. Two of

these member checks were completed in person one year following fieldwork as these

individuals were in Toronto attending a conference on regenerative medicine. The data collection

and analysis methods used to capture and review this data are outlined. The ethics review process

is presented, looking at ethical concerns that arise in the course of qualitative research

(confidentiality, anonymity, risk) and how these were addressed.

2.2 Case Study Methodology

The case study approach is an in-depth investigation of a single individual, group, or event [73],

allowing researchers to explore complex phenomena within their context using a variety of data

sources [74]. There are three conditions for researchers to consider when deciding on applying a

case study approach [75]

1. What is the form of research question? (How Vs. What)

2. Does the study require control of behavioural events? (Control Vs. no control)

3. Does the study focus on contemporary events? (Current Vs. Past events)

Research questions that focus on “how” or “why” are explanatory and are suited to case study

analysis. Questions such as “what” or “where” are descriptive and best suited to the use of

alternative methods such as surveys. Given that this research will explore how clinical translation

of NeuroRM within India is taking place, the case study is an appropriate methodology.

Furthermore, as this study does not require control of behavioural events and focuses on

contemporary events, these considerations further support the use of this method.

19

Within case study research, an overarching case can be composed of “units of analysis” (Feagan

et al (1991)). Mayhew (1980) [76] writes that the units of analysis are specific subgroups of the

overarching case and not on the individuals themselves. Researchers can better draw from these

groupings to understand the nature of the whole process better than attempting to draw from the

individual experiences of each interviewee. In this study the case is defined as the phenomenon

of clinical translation of Neuro-Regenerative Medicine within India. The units of analysis are the

stakeholder groups: Researchers, clinicians, private firms and regulators/reviewers. The role of

each subgroup is discovered in this work and linked to the larger phenomenon of clinical

translation.

2.2.1 Limitations of the Case Study Methodology

One limitation of this method is ensuring the validity of a study. Validity involves determining

the degree to which a researcher’s claims about knowledge of a given phenomenon corresponded

to the reality, or participants’ perceptions of reality [77]. To ensure validity of a study Neuman

(2003) [78] has outlined strategies to maximize validity such as Triangulation, Peer Review and

determining my position in relation to the study.

Triangulation refers to the use of multiple sources of data to confirm emerging findings. This

research incorporates data from interview transcripts, field notes and secondary data sources.

Secondary data sources refer to documents from Indian government agencies, including mission

statements, annual reports and regulations on regenerative medicine development. Institutional

websites, researcher profiles and publications were also incorporated into the data collection to

determine persons of interest and identify emerging NeuroRM technologies within India.

Researcher’s position refers to potential biases held by the investigator that may impact how data

is perceived and interpreted. To overcome this limitation, I reflect below on potential biases held,

how these may impact my analysis of the data and strategies to address these biases.

Before starting my master’s degree research I obtained an undergraduate degree focused on

genetics and health studies. In this program, discussions of regenerative technologies such as

stem cells, gene therapy and tissue engineering were undertaken from the researcher perspective.

Discussions in this field centred on biological facets of emerging technologies and not on the

context within which these advances are developed and eventually deployed. Additionally, as a

research assistant with the McLaughlin-Rotman Centre for Global Health, my work centred on

20

NeuroRM development from the perspectives of Canadian researchers. I have worked to ensure

that perceptions of these stakeholders have not impacted my perception of translation in other

contexts. For example, what is deemed as sufficient proof in one context may differ in another.

As an investigator, I have situated myself in the work to be aware of how my own perceptions of

the themes discussed in this research impact my analysis and reporting.. I have worked to

minimize bias by relying on interviews with experts that have played diverse roles in NeuroRM

in India including scientists and physicians.

Peer review refers to the engagement of advisory committee members and students within my

research group at the McLaughlin-Rotman Centre for Global Health. I had the opportunity to

present updates on my research before data collection, during my analysis and upon completion

of early stages of this manuscript. Input at each stage of this process has helped direct the work

and informed the final product. Students where engaged as well and provided valuable

knowledge regarding literature to consult, methodological concepts and input on analysis

methods.

2.3 Sampling Methodology

The sampling method applied here is based on the works of Glaser, Straus and Sandelowski [79-

81]. Glaser and Strauss developed the concept of Theoretical Sampling in 1967 in which

researchers simultaneously collect, code and analyze data. Ongoing selection criteria shift based

on emerging codes and themes. In later works, Glaser defines Selective Sampling as:

The calculated decision to sample a specific locale according to a preconceived but reasonable initial set of dimensions (such as time, space, identity or power) which are worked out in advance for a study.”

Sandelowski combines the two approaches, suggesting that centres and persons of interest are

identified through a targeted search in advance while allowing for sampling of more individuals

as the study progresses. Here, participants were selected based on the criteria articulated below.

New participants were identified based on recommendations from respondents.

2.3.1 Selection Criteria

Persons of interest were identified through a search of publication databases including Pubmed,

Web of Knowledge, Web of Science, Medline and Scholar’s Portal. Three search criteria were

21

cross-referenced when conducting the search: 1) type of technology 2) condition studied 3)

location of study. In the first criterion, search keywords included “regenerative medicine”, “stem

cells”, “tissue engineering”, and “genetic engineering”. In the second, conditions of interest

referred to research related to neurodegeneration with terms including “neurodegeneration”,

“Parkinson’s”, “axon degeneration”, “spinal cord injury”. Criterion three was set to locate all

studies within India. Hubs of NeuroRM activity were identified and cities selected based on this.

Clinicians affiliated with research groups were identified beforehand where possible, or

contacted while travelling through referrals from initial participants.

Online resources from the Indian Council of Medical Research (ICMR), Department of Science

and Technology (DST), Department of Biotechnology (DBT), Council for Industrial and

Scientific Research (CSIR) and the Drug Controller General of India (DCGI) were reviewed to

identify institutions / persons of interest. This assisted in identifying government contacts in this

study.

2.3.2 Participant Recruitment:

Persons of interest were emailed invitations to participate in this study and provided with an

overview of the objectives of this work. Individuals were asked to discuss their views and

experiences in the field of NeuroRM. Respondents were told that interviews would be

undertaken in a location of their choosing such as their office, lab or clinic. These sessions were

approximately one hour and participants were informed that care would be taken to ensure

anonymity was maintained. A one-page summary of the study was attached (See Appendix A).

Two weeks later, non-respondents were contacted by phone. Concurrently, appointments were

set with confirmed participants. A final round of calls was undertaken, one week later, where

remaining non-respondents were contacted.

2.3.3 Characteristics of Participants

Twenty-three participants were grouped into four categories; basic scientists, clinicians, policy

maker/reviewer and private firms (see table 2.1) and conducted with participants in 5 cities (see

figure 2). Patient groups were not engaged in this study as the focus of this work is on engaging

the developers and providers of NeuroRM technologies to determine barriers and strategies in

moving these technologies forward. As outlined in Section 1.3, this refers to the T1 barrier.

22

While engaging patients is a potential next step for translation researchers, this is outside the

scope of this project. Patient perspectives will be critical in future research related to challenges

in knowledge translation, uptake of proven technologies into standard practice referred to as T2

barriers. The four groups outlined in this work were generated based on preliminary research and

informed by referrals during data collection. Categories are explained below and numbers of

individuals from each group are presented. Many participants had experience in more than one

area. For example, one policy maker with the Department of Biotechnology also discussed their

experiences conducting research with stem cell. In the descriptions below, the numbers of

participants reflect the total number of individuals working within that group. Accordingly, the

final total is greater than twenty-three

Basic Scientists

Nine scientists working in publicly funded institutions were interviewed. These included

researchers with university groups receiving funds from the Indian Council of Medical Research

(ICMR), the Department of Biotechnology (DBT) or Department of Science and Technology

grants. These include universities, public hospitals and non-profit organizations that receive both

government funds and private support. One institution, LV Prasad Eye Institute (LVPEI), is a

non-profit group that obtains funds from both government grants and through philanthropic

donations.

Clinicians

Eight clinicians were interviewed within publicly funded hospitals and research institutions.

Seven of these were involved with basic science studies and transitioning these into clinical

research at the time of data collection. This category encompasses physicians who collaborate

with researchers and responsible for administering treatments and monitoring patients after

surgery.

Policy Makers / Research Reviewers

Thirteen government officials and research ethics board members were interviewed. Four

individuals involved with policy makers from the Indian government and nine members of

research ethics board members were engaged. These represent individuals involved with setting

23

regulation and reviewing protocols submitted to the government. One example of a policy

maker, whom we spoke with was involved in drafting guidelines with the DBT Stem Cell

Oversight Committee and ICMR/DBT guidelines on stem cell research in 2006. Reviewers are

stakeholders who, through their affiliation with government groups, such as the ICMR, receive

submissions from colleagues for review. In this study, reviewers were either clinicians or

researchers involved with the review process.

Stakeholders within Private Firms

15 interviews were completed with three RM private firms, four with scientists and eleven with

clinicians. These are three distinct institutions, however one maintains ties with a private

hospital. The clinicians interviewed are included because of their work in one of the private firms

and within clinical studies therein. Private institutions are groups not supported through public

grants. Researchers and clinicians in private firms are grouped separately from those within

public institutions because of divergent foci, funding source and commercialization practices.

24

Table 2-1 Institutions Visited (April – May, 2009)

Institution visited Targeted Disorders Approach Private Firm

Nichi-In Centre for Regenerative Medicine

Spinal Cord Injury (SCI), Motor Neuron Disease, Parkinsonism (PD)

Autologous bone marrow derived stem cells (BMSCs)

Reliance Life Sciences Alzheimer's, SCI, PD, Multiple Sclerosis (MS)

Allogenic SC, Autologous SC, Scaffold use

Stempeutics SCI, Ischemic Stroke Lesion, PD Allogenic Stem Cells

Hospitals

Apollo Hospitals SCI, Motor Neuron Disease (MND)

Autologous Stem Cells Bharathiraaja Specialty Hospital SCI, MND Lifeline Hospital Multiple Conditions New Hope Medical Centre Multiple Conditions

St. Philomena's Hospital Multiple Conditions Autologous SC, embryonic stem cells, BMSCs

LV Prasad Retinal/Corneal degeneration oral mucosal cells, tissue transplantation, autologous SC

Academic Institutions L.T.M.G Hospital SCI, MND Autologous SC National Centre for Biological Sciences

Stroke lesion, stem cell migration studies

Autologous SC, embryonic SC

National Institute of Mental Health and Neuroscience

A.L.S Models, SC migration, Alzheimer's Autologous SC

All India Institute of Medical Sciences SCI, MND, Stroke Autologous stem cells

Government Agencies Department of Biotechnology Indian Council of Medical Research

25

Figure 2 Map of Data Collection Sites

Data Collection

2.3.4 Interviews

Semi-structured face-to-face interviews were undertaken with twenty-two participants and one

by phone, for a total of twenty-three interviews. The first week of interviews were led by Mark

Messih and Dr. Claudia Emerson, identified as MM and CE respectively within interview

transcripts. Dr. Emerson was present for the first week of data collection and guided the initial

interviews. She provided support in developing interview and analyzing skills. I completed the

remaining interviews independently. An interview guide (Appendix B) was developed composed

of questions related to the objectives of this study:

26

1. To identify the stakeholders involved in translation, roles of each in clinical translation

and challenges faced by each group during translation.

2. To describe India’s regulatory environment concerning NeuroRM translation by


3. To determine the role of collaboration in clinical translation by mapping where

partnerships develop and studying how partnerships impact translation.

2.3.5 Overview of Interview Progression

Interviews with participants began by describing their research and/or clinical activities. Next,

participants discussed the regulatory environment, reflecting on past interaction with regulatory

agencies, recurring ethical issues in their work and how these were addressed. One interview

guide was used with questions discussing research, clinical and policy facets of translation.

Questions were selected from the guide based on the participant’s role in translation. For

clinicians, questions centred on clinical trials and interaction with patients. Likewise, interviews

with policy makers focused more on translation regulation. The interviews concluded with

discussions of next steps for their work.

2.3.6 Field notes

Ten of the twenty-three face-to-face participants requested that the conversation not be tape

recorded but allowed for note taking to take place. Three participants from a private firm

requested that they use their own tape recorder and transcribe the material themselves, however

notes were taken in this session. They then mailed the output of this discussion as a series of

questions and responses. The other seven participants articulated personal preferences for not

being tape-recorded. Notes were reviewed after each interview then typed to facilitate analysis.

27

2.4 Data Analysis

Interview transcripts were analyzed using Atlas.ti version 5.2, a program that allows for

qualitative analysis through coding of interview transcripts. A thematic analysis was performed

where codes were generated and grouped into three themes: regulation, translation and

collaboration. Analysis was divided into the following three steps [82]: Immersion, Open

Coding and Axial Coding. I immersed myself in the data during transcription and collation of

notes and reference materials. Immersion refers to the reading and rereading of data from

multiple sources to increase the researcher’s familiarity with their findings. Through immersion,

researchers are better able to discern emerging themes and organize large amounts of data.

Listening through interview recordings, reviewing notes and studying policy documents were

important in this step. Atlas.ti was used to generated codes based on each idea. Examples of

codes include barriers to collaboration and measuring clinical outcomes. A list of codes and

rationales for each are outlined in Appendix C. Open coding consists of identifying broad

concepts and ideas that emerge from the data sources. Identifying codes for each idea were noted

in the margins of each transcript. Axial coding refers to specification of open codes. One

example would be to take the open code of barriers to collaboration. Axial codes include

financial barriers to collaboration and cultural barriers to collaboration.

Field notes were typed and were coded using the same steps as interview transcripts. Secondary

sources including research papers, government documents were also analyzed in this process.

These documents were identified before hand through online searching and were also

recommended by participants during data collection. Documents were read and annotated by

hand to understand the content and scope of these works. One example is analysis of the Indian

Council for Medical Research Guidelines on Stem Cell Research and Therapy. In reviewing this

document, I noted which sections discuss oversight, categories of research and government

involvement in stem cell regulation. This analysis provided an initial framework, which I applied

during interviews. In my discussions of these ICMR guidelines, for example, possessing

knowledge of the three categories of permissible research in advance, helped in discussing

regulations with participants.

28

2.5 Research Ethics Review

This research represents one part of a multi-national study that was approved by University of

Toronto Health Sciences II Research Ethics Board on March 14, 2007. An informed consent

form (See Appendix D) was emailed to participants in advance to review. In the consent form,

the investigators, aims and our source of funding (CIHR) were outlined. At the start of each

interview, the project was explained and informed consent reviewed with participants. All

interviews that were digitally recorded, were transcribed and stored on a password-protected

computer. Printed transcripts and related materials were stored in a locked cabinet at the

McLaughlin-Rotman Centre for Global Health. Only members of the research team had access

to this data. Any potentially identifying information that can reveal the identity of a participant is

removed. Each participant was assigned a code and the final list of participants and codes is

stored securely with digital copies of the interviews.

Study materials will be stored for five years following completion of the study. Information on

the institutions visited and the research projects underway were included as this information is

publicly available on institutional webpages and C.V.s. When using quotations that reflect

participant’s opinions on translation within India, the description of participants was kept to a

minimum, identifying the broad type of research or clinical activity they are involved with. The

risks of participating in this study were deemed minimal.

In discussing RM technologies such as embryonic stem cell research, participants may share

views that differ from colleagues operating in other societies. To address this, care has been

taken, as outlined above, to ensure confidentiality and anonymity of these discussions.

29

Chapter 3 Results

3.1 Introduction

In this chapter I will outline the most commonly targeted neurodegenerative disorders to provide

context of where NeuroRM technologies are being applied and why. Three of the most recurrent

conditions being targeted by NeuroRM strategies are mentioned below. These were determined

based on interview data and from secondary sources (i.e. statistics, reports and surveys).

Identification and discussion of conditions being targeted by scientists and clinicians is important

for two reasons. Firstly, this identifies what neurodegenerative diseases are already impacting the

population and where India is directing research activity. Secondly, as one of the first nations to

translate in this field, Indian scientists and clinicians have developed criteria for identifying

conditions that are best suited for NeuroRM application. Based on the conditions discussed here,

criteria for choosing conditions to target are as follows:

1. Localized site of injury/degeneration to target the intervention

2. Ability to observe changes following clinical studies

3. Burden of the condition of interest on patients

Next, the role of each stakeholder group in clinical translation of NeuroRM research is presented.

Identifying information for participants has been removed. In certain cases, information available

through institutional websites is presented as the data is publicly available. Government agencies

involved in translation are identified and their role in translation outlined. Collaboration in

translation, focusing on where collaborations are developing and how these are initiated is

presented.

3.1.1 Spinal Cord Injury (SCI)

SCI represents a promising target for NeuroRM for several reasons. Firstly, the prevalence and

incidence of SCI is rising within India, creating a need for new therapies that restore function.

Statistics have shown the incidence of road traffic injuries is rising, particularly for youth aged

20-29 [83]. Disability, caused by accidents, is estimated to be prevalent in 35.1/100,000 of the

30

population, approximately 400,000 individuals nationwide. Researchers, interviewed in this

study, also reported treating spinal cord injuries caused by road accidents. Below is one

reflection from one interviewee, working on autologous stem cell treatment for SCI patients:

[We treat] Road traffic accidents, falls mostly. In the US I guess you would see a lot of other kinds of injuries, assaults, gun shots things like that. So far, [that is] not very common here. We have accidents, mostly road traffic accidents…

In rural settings, SCI due to falls, workplace accidents and highway collisions are the most

recurrent causes of injury in young adults. Injuries in rural areas pose additional challenges for

clinicians and researchers. There are difficulties when following up with patients and providing

long-term care. According to one clinician who is collaborating with researchers on stem cell

trials for spinal cord injury, patient follow up and rehabilitation is a challenge in India’s

healthcare system:

For patients who live right next door to the hospital, who are still not coming in for follow up, it's attitude thing, it's an absence of awareness, you know, and the people in the family who are working, there's nobody who is available to bring the patient to the hospital. We don't have a social health system that can give you a domiciliary service for someone to go home and see the patient and do something useful

In addition to the demand for novel treatments, SCI is seen to be an ideal target for NeuroRM

strategies. When one portion of the spinal column has been injured, physicians can better target

an intervention, as they know where to administer cells. According to one clinician-scientist with

in a private firm, this feature makes spinal cord injuries a potential candidate for NeuroRM

therapy:

One thing that we do…is the spinal cord injury in which the primary injury has been set right. So there is no compression of the spine…and why not [target other] diseases? Because for example muscular dystrophy. The etiology is not in a single focal point and if you take for example motor neuron disease. It is widespread, where to apply this we don't know….

3.1.2 Corneal and Retinal Degeneration

Corneal and retinal degeneration are included in this study for two reasons. First, the eye is a

complex organ that has many tissue types including nerve, pigment and receptor cells. Damage

to one part of the eye affects other portions of the eye. While the cornea is not specifically

neurological, the eye is treated in the same clinic for most of its conditions and it was useful to

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consider the eye as one unit. Second, within India, the burden of degeneration of nerves and the

surface of the eye is critically high, and there will be an increasing demand for regenerative

medicine interventions for these diseases. As I will outline in this chapter, NeuroRM translation

involves adaptation of existing knowledge in related fields, accordingly, new corneal

technologies may prove beneficial in other areas of the eye and eventually in the central nervous

system. Impaired vision and blindness drastically reduce the quality of life of those afflicted. The

existence of more than 1200 public and private eye care facilities in the country [84] reflects the

high prevalence of eye related disease and estimates of blindness prevalence range from 4.2% to

13.7% [85]. According to research undertaken by one interviewee, common causes of

degeneration include accidental damage, aging and infection [86]. Participants in this research

have discussed why the eye is an optimal cite for NeuroRM therapies. Clinicians can readily

observe changes in the eye over time by looking directly into the eye and measuring reactivity to

light, cloudiness and scarring. Additionally, researchers can apply existing surgical practices to

administer stem cell/scaffold combinations onto the eye. The existing treatment for corneal

damage involves tissue transfer, where tissue from a donor eye is placed on the damaged eye.

The limitations of this approach are reflected in the interview of one participant who is

transplanting autologous stem cells for corneal damage:

We all knew that we are doing the limbal transplantation because it has stem cells and that they will regenerate the corneal epithelium, but if we know that they are stem cells and if we know how to grow them, can we put these two things together and then, grow in the lab instead of taking large amount of tissue that needs to be harvested.

3.1.3 Movement Disorders – Parkinsonism (PD)

It is anticipated that more than 1 million Indians will live with PD by the year 2016 [87].

Additionally, clinicians are witnessing increasing numbers of patients who present in later stages

of PD. Participants cited changes in cultural and demographic norms that are causing elderly

individuals to be living alone with movement disorders. One clinician interviewee below

discusses this:

To understand, in India also, the gray population is increasing. We have a lot of elderly people now, much more than we used to have 20 years ago…. The aging population we are now encountering now we know that these [cases] are due to Parkinson’s and Alzheimer’s. [These] are getting more and more understanding, understanding is more. Also there is this system of having nuclear family…. Children [are] not staying with the

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parents and the problems really are getting confounded because they are left behind to fend for themselves.

PD conditions are well suited for regenerative medicine strategies because it is caused by

degeneration of a specific cell type, dopaminergic neurons. In one interview with a researcher ,

who is beginning to apply stem cells in clinical trials, candidates for NeuroRM intervention were

discussed:

Well Parkinsonism is defined as one phenotype, but in reality it has a number of other phenotypes, what we have discovered…. It is very specific way, of a specific cell type, a specific way of going after it, which may not be the case for many other cells, diseases.

3.2 Roles of Stakeholders

3.2.1 Basic Research Scientists

Academic institutions have existing resources and expertise that new studies build on.

Equipment, personnel and funds are applied to explore the safety and efficacy of new

interventions. Lander et al. (2008) have discussed India’s proficiency in adapting existing

resources to develop stem cell research. This study, on NeuroRM translation in India, confirms

these findings in the context of NeuroRM development. In one interview with a stem cell

neuroscientist, the participant discusses the branching of NeuroRM studies from existing

resources:

Yeah, and clinical aspect, see well you have, you need to maintain a good lab where you can make these stem cells properly and you can make sure that there's no genetic mutation. You need the facility that government covers. As far as the clinical work is concerned…we already have a huge neurosciences department.

Scientists interviewed report that collaboration between scientists in other disciplines catalyzes

expansion into NeuroRM studies. The role of collaboration in catalyzing basic science

innovation is further outlined in section 4.4.

3.2.2 Research Focus

Studies are divided into two categories; characterization studies and protocol development.

Characterization studies focus on fundamental principles of NeuroRM technologies. Protocol

development studies are defined as research focused on the clinical application of NeuroRM

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technologies that are viewed as safe and proven. These are conducted with the view that there is

sufficient evidence to warrant moving from the laboratory into animal studies and shortly,

towards human application.

3.2.2.1 Characterization Studies

Scientists that are leading characterization studies believe that there is still insufficient

knowledge of how NeuroRM interventions function to begin using them in clinical studies.

Researchers articulated that stem cell research is promising, but our knowledge of how these

interventions operate is limited. One interviewee outlines how their research seeks to determine

how stem cell grafts behave in vivo:

We are asking 2 questions. Okay, whether this [stem cell] is inducing host regeneration. …If it [does] induce, [how do] the graft cells help or mediate host regeneration…? Maybe, the host is providing all [the] microenvironment and internal milieu for the graft to survive and the graft in turn [is] expressing various neuro-trophic factors, which in turn also helps the host, to regenerate itself… So now what I think maybe… these graft cells …induce a functional recovery by [promoting] host regeneration.

If secreted factors promote regeneration and not the cells themselves, scientists can generate

these factors and administer them without transplanting cells. Regenerative medicine

technologies can also be applied as models to understand the causes and progression of

neurodegenerative disease. In the following example, information on the stakeholders is

included to illustrate where partnerships are forming. The findings of this partnership have been

published. Furthermore, the statements below do not reflect personal views or beliefs of the

participants. One NIMHANS researcher studying disruptions in the chemical composition of

cerebrospinal fluid (CSF) in Amyotrophic Lateral Sclerosis (ALS) discussed the advantages of

applying RM in basic science studies over using animal models of disease.

If we infuse the [cerebrospinal fluid] from ALS patients into adult ... we have produced specific motor deficits in the adult rat, which are easy to measure.... the next question we asked ...could we isolate whatever is present in the ALS CSF, which produces these specific changes in the spinal cord? And so for that we needed to develop a good bioassay system. We could not get that just using the rats... You need hundreds, thousands of rats.

Another scientist-clinician, studying embryonic stem cell use in the nervous system, discusses

the promise of stem cell research but believes more research is needed within India before

transitioning into clinical studies:

34

I believe that we need to be very sure that it works first.... How will they grow when they are in vivo? What are they going to produce inside the body…. So before we put in these cells into anybody we really want to be sure about the viability of these cells…. Stem cell [research] in India is in…the conceptual stage, the really early stages in India.

3.2.2.2 Protocol Development

These are studies that centre on determining best practices for administering NeuroRM

interventions to patients. Researchers believe that there is sufficient evidence in the literature to

warrant moving into human studies. In one interview with a NIMHANS scientist-clinician:

I would be first looking for clinical benefits. I'm not going to look into whether… stem cells I have injected have become a kind of [cell] with the host nervous system, [or] neurons which are involved in the process, or how are they integrate….

Another researcher with a centre for cellular biology is applying established protocols for cell

transplantation:

But even before we knew anything about stem cells, quite a bit of autologous bone marrow transplant has been going on in this country for the last 30 years in cases of severe anemia and that's pretty standard.

In another interview, one researcher who supervises clinical studies on limbal stem cell

transplantation discussed how research is building on existing good practices.

Okay, the guidelines are like this, if there is already a precedence of human trials, you don't have to reinvent the wheel again, except that the cells that you use, you have to show that they are of adequate quality, the cell type that you are talking about.

The section above focused on basic researchers in NeuroRM translation. Two categories of

research activity are outlined grounded in the perspectives of study participants. The next section

discusses the role of clinicians in translation.

3.2.3 Clinicians

Clinicians lead human studies through partnerships with institutions that provide materials for

clinical therapy. We have interviewed scientists with the Nichi-In Centre for Regenerative

Medicine (Nichi-In) in Chennai, India and three collaborating physicians from two different

health centres. In this partnership, each clinician receives autologous stem cells for spinal cord

injury patients and is responsible for administration and follow-up with the patient. The excerpt

35

below is taken from an interview with a Nichi-In administrator discussing partnerships with

clinicians:

To the patients that come from abroad who want to undergo stem cell therapy, we do provide services for them. So it depends upon the doctors. So initially we send off the case and the surgeons, so those who want cells, we provide cell…we also give them the data.

One clinician who partners with a private company to deliver stem cell therapies highlights how

the partnership with the firm began and what his role was:

So as of now, I have done three subjects on whom I have done stem cells with…. Since I've gotten a lot of patients with spinal cord injury and paraplegia, I went through a lot of articles on the net and through the net I got in touch with NCRM and got into what they were doing and got interested in the whole thing and I started doing stem cells myself. So now I have done, as of now I have done stem cell therapy for 3 patients, all 3 youngsters who have spinal cord injury … in the lumbar spin.

Alternatively, clinicians are located within multidisciplinary institutions that have both clinical

and research departments. Examples include NIMHANS, L.V. Prasad and Stempeutics based at

Manipal University and Manipal hospital. This arrangement appears to facilitate discussion,

collaboration and transitions technologies from the bench into the clinical setting. One

Stempeutics researcher discussed the need for partnering with clinicians during clinical

translation:

We have done everything with the mice, rats; experimental, very early studies underway. Now the time has come to join hands with the clinicians, so it is teamwork. So I am a basic scientist, then we take help of the clinicians and the surgeons. So it is a teamwork, we form protocols and then it goes to the patient. So ultimately, it should be translated into patients for application.

In private and public partnerships, clinicians are involved in the design and execution of clinical

studies. The section above has presented data on clinician involvement in translation. Next,

barriers that arise in clinical studies are presented.

3.2.3.1 Barriers to Clinical Development

The two barriers to clinical development, reported by interviewees, are challenges in patient

follow up and outcome assessment during clinical trials. All clinicians engaged in this research

discussed, at least, one of these concerns. According to clinicians interviewed in this study,

patients are lost to follow up because it is challenging for patients to come for regular

36

appointments due to the large distances some recipients are travelling for treatment. Physicians

have reported patients travelling from rural communities to larger cities for treatment. Below is

an excerpt taken from an interview with a spinal cord surgeon who leads clinical studies using

stem cell transplantation:

MM: Why do you think the follow up with patients after surgery is so poor?

X13: Well there are 2 reasons for that. One is you know, it is good, in the west because you follow up in the same place where you have treatment. In India it's not like that, you have … patients coming from the Northeast and they travel for 2 days before they get here and you know, there is no follow up possible there. For patients who live right next door to the hospital who are still not coming in for follow up, it's attitude thing, it's an absence of awareness, you know, and the people in the family who are working, there's nobody who is available to bring the patient to the hospital.

Physicians reported challenges in assessing patients using qualitative outcome measures.

Reasons cited include limited access to equipment, lack of patient compliance and insufficient

funding for long-term assessment. Studies are forced to rely on qualitative outcome measures

over quantitative measures. In the quotation below one clinician as a patient consultant with a

private firm reported difficulties in following up with recipients after treatment:

We say that we would be happy if you have evoked potentials, somatosensory potentials, neuro-conduction studies, urodyamic studies to look at how the bladder function happens. But the vast majority of these patients, these patients don't get them done…and they don't do it…so we really don't know. So what we are left with is, just looking at subjective improvements of patients.

The section above discussed the role of clinicians in translation and presented challenges faced

by physicians during clinical studies. The next section focuses on private firms in translation.

First, I will outline how initial R&D development differs from the research encountered in public

institutions. Next I will discuss clinical studies and generating important data on structuring

protocols. Finally, NeuroRM products from interviewed institutions are presented with

information on the product and the process firms undertook to commercialize.

3.2.4 Role of Private Firms

In this section data collected from interviews with three private firms, Stempeutics Inc., Reliance

Life Sciences and the Nichi-In Centre for Regenerative Medicine is presented. Preclinical

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research activity is reviewed followed by a discussion of commercial products that are currently

offered to treat neurodegenerative disorders.

3.2.4.1 Preclinical Research

According to our participants, research targets development of commercializable products.

According to one participant from Reliance Life Sciences (RLS), research areas are chosen based

on their potential to translate into products:

RLS is focused at bringing stem cell therapies that would cater to unmet medical needs…. RLS also looks at whether the chosen area would benefit the nation by providing access to a larger patient population by providing affordable therapy. The research and development efforts of the Regenerative Medicine group at RLS is to look at the possibility of stem cells substituting a deficiency and providing a long term remission, if not cure. RLS is working on areas where research and development can translate into concrete products for the marketplace.

This is being pursued through two types of research. These categories are discussed below and

are based on review of these institution’s publications and interviews:

• Adaptation studies

• Clinical protocol development

In adaptation studies, researchers investigate the use of existing technologies to treat

neurodegenerative disease. For example, The Nichi-In centre for Regenerative Medicine has

adapted epithelial cell culturing methods from Japanese collaborators for use in India. Below is

an excerpt from an interview with one researcher from the centre who is discussing new

technologies for storing and transferring stem cells over large distances within India. This is

important, as patients from rural areas must travel to urban centres for treatment:

Now what we have done is, we have adapted the technology from Japan and we are able to grow the corneal epithelial precursors in our laboratory in the same way…. What we have added as a value to the already existing findings is that we have made the corneal epithelium being transported in Indian local conditions taking 24-96 hours. In just a small package that's it, not cold preservation. This is very much of paramount importance in the Indian situation.

In characterization studies, researchers seek to answer questions including: which cell types are

most effective at promoting regeneration? When and where should these be administered?

According to one researcher from Stempeutics, characterization studies using animal models are

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undertaken to develop clinical protocols and demonstrate efficacy of stem cell use in spinal cord

injury:

And we are also showing in Stem the rat model of the spinal cord injury, that if we inject these stem cells into the site of the spinal cord, periphery, or at the site of injury, there is a good regeneration of neural tissue.

Furthermore, private firms have reported challenges in publishing data on human studies without

having conducted animal studies in-house. One interviewee indicated the benefits of the using

canines for spinal cord injury and said:

It will be [in] canine models and we're looking at giving this therapy for them because it's easy to follow them…Just to know whether it works because we've done a lot of work in human patients, and I told you the impediments of why we cannot publish them in a journal… So this is a very small study of doing it animal models [to] see whether it works so at least we'll get a scientific background to what we are doing.

Reliance Life Sciences (RLS) reported a similar experience in developing stem cell products.

According to one scientist with the firm:

RLS carried out a basic R&D groundwork with our group of researchers to see if the area chosen is workable and arrive at the technical feasibility and capital investment required…. RLS has been able to successfully demonstrate reasonable efficacy in animal models. RLS has received approvals from the local stem cell ethics committee, Indian FDA and the Drug Controller General of India for clinical trials.

Within these institutions, research and development has generated commercial products that are

discussed in the next section.

3.2.5 Commercial Products

Private firms believe that there will be a demand for neuroregenerative therapeutics within India.

According to one clinician from Reliance Life Sciences, will benefits a great deal from

regenerative medicine development:

Regenerative Medicine, comprising stem cell therapies and tissue-engineered products, is at a nascent stage in India. The areas where stem cell therapies have potential are in ocular, cardiovascular, and neurological disorders. The incidence of several life threatening and life style diseases is significant in India…. Therefore, India has the potential to derive significant benefits from stem cell biology research

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Private institutions have already begun generating products for commercial use to treat

neurodegenerative conditions. Below, three technologies from Reliance Life Sciences,

Stempeutics and Nichi-In Centre for Regenerative Medicine are discussed.

3.2.5.1 Reliance Life Sciences – ReliNethra©

ReliNethra© is an autologous bio-engineered composite limbal epithelial graft for corneal

disorders. This product is marketed to treat conditions including chemical burns and mechanical

injuries to cornea. Autologous human limbal epithelial cells are cultured on human amniotic

membrane. The extracellular carrier matrix is prepared by Reliance Life Sciences and they

undertake cell culturing as well. The kit provides clinicians human amniotic membrane with

cultured autologous limbal cells grown from limbal explants. The firm has obtained approval

from the Drug Controller General of India and Food and Drug Administration to commercialize

this product. It has also been patented with the World Intellectual Property Organization [88].

Figure 3 Relinethra Epithelial Graft Kit

3.2.5.2 Stempeutics – Autologous and Allogenic Bone Marrow Culturing Services

Stempeutics has completed pre-clinical studies for the use of human bone marrow-derived ex

vivo cultured adult Mesenchymal stem cells in allogenic settings. With approval of the Drug

Controller General of India (DCGI) and Indian Council of Medical Research (ICMR), they have

completed multi centric phase I/II combined double blind randomized allogenic clinical trials on

acute myocardial infarction and critical limb ischemia. Stempeutics recently published results of

a clinical study on autologous bone-marrow-derived Mesenchymal stem cell transplantation in

Parkinson's disease [88]. The following is taken from their findings published in the journal

Translational Research

A subjective improvement was found in symptoms like facial expression, gait, and freezing episodes; 2 patients have significantly reduced the dosages of PD medicine.

40

These results indicate that our protocol seems to be safe, and no serious adverse events occurred after stem-cell transplantation in PD patients.

The first wave of commercial products for neurodegenerative disease is anticipated to enter the

market by 2012. Following data collection, Stempeutics announced plans to collaborate with

Cipla, an Indian pharmaceutical firm, to market stem cell based therapies for critical limb

ischemia [89]. It is anticipated by Stempeutics clinicians interviewed by the press, that this

collaboration will extend to research in other areas of study at Stempeutics [90].

3.2.5.3 Nichi-In Centre for Regenerative Medicine (NCRM) – cell expansion services

NCRM provides cell culture and expansion services for patient autologous stem cells to treat

conditions including spinal cord injury and neurological trauma [91]. The excerpt below is taken

from the NCRM homepage (http://www.ncrm.org/index.htm) and outlines services provided by

NCRM:

NCRM provides autologous bone marrow/peripheral blood stem cell isolation, enrichment and expansion services to partner hospitals within India. The patients are admitted in the hospitals from where the bone marrow or peripheral blood is harvested and transported to NCRM. The isolated, enriched, expanded stem cells are delivered to the hospital where they are administered to the patient

Case reports have been presented on clinical studies using autologous bone marrow mononuclear

cells in spinal cord patients [92]. Below are findings from a clinical study involving 108 spinal

cord injury patients presented at the Thirteenth Annual Meeting of International Society for

Cellular Therapy.

Out of the 108 patients in whom the ABMMC [autologous bone marrow mononuclear cells] was used, none of the patients had any adverse reaction to the cells, at least 14.11% of patients reported at least 2 grades of improvement in motor power and 4.7% of patient were able to walk independently.

16.47% of patients reported subjective sensory improvement, none of the patients had abnormal sensations such as allodynia.

9.41% of patients had improvement as documented by urodynamic studies.

The factors determining outcome which could be the age of patients, level of injury, time interval between injury and ABMMC injection, dosage of stem cells injected etc., need to be evaluated in future studies.

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The roles of researchers, clinicians and private firms have been reviewed. Challenges faced by

these stakeholders were also stated. The next section focuses on regulation and oversight of

NeuroRM translation. First, the ethical concerns raised by researchers and clinicians are outlined.

Second, government agencies involved with translation are introduced.

3.2.6 Neuro-ethical Concerns

Interviewees were asked to discuss recurring ethical challenges raised by their research and how

these are addressed. Sources of materials, donor consent and data sharing were cited as the most

common ethical challenges in NeuroRM translation. This section discusses each concern and

combines the experiences of participants with excerpts of relevant guidelines that govern ethical

oversight of NeuroRM translation.

3.2.6.1 Sources of Materials

Collection of materials for NeuroRM studies presents ethical challenges according to researchers

interviewed in this study. During institutional review of protocols, Research Ethics Boards

(REBs) review the source of tissues, how material was collected and adherence to government

standards during collection. One scientist working with embryonic mouse stem cell lines instead

of human cell lines reflected on past experiences with ethics review boards when generating a

human stem cell line:

If you’re generating a new line there of course issues come up.... Why do you want to do it? Can you not use an existing line? Why should you want to generate a new line? …. So if you are using an existing line, the criteria would be that, that line has been derived with informed consent.

The government of India requires that stem cells be registered and collected in agreement with

established good practices as defined by the Indian Council for Medical Research and

Department of Biotechnology. The government recommends that Institutional Committees for

Stem Cell Research and Therapy (IC-SCRT) be established in each centre and a National Apex

Committee for Stem Cell Research and Therapy (NAC-SCRT). When transferring materials

between groups, a material transfer agreement (MTA) is required. According to ICMR

Guidelines on Stem Cell Research and Clinical Therapy:

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Section 4.4

All established human stem cell lines from any source, imported or created in India, should be registered with IC-SCRT and NAC-SCRT. Permission for import/procurement from other Indian laboratories shall be obtained from IC-SCRT. The investigator shall ensure that the cell line has been established in accordance with existing guidelines of the country. An appropriate MTA shall be adopted for the purpose.

3.2.6.2 Informed Consent

Clinicians face challenges when obtaining informed consent for several reasons. First, how well

can the patient understand the study when enrolling in a clinical trial? Participants in this study

expressed concern that patients are not giving informed consent to enroll in clinical studies. One

researcher studying stem cell use in Parkinson’s Disease faces these challenges in clinical

research and highlights how disparities in education impact how patients understand the trial and

how data is presented:

See I was just looking at the, the consent and information consent, informed consent form that we take and ours… has to be in the local language, patients can understand because not many people, in the patients are, you know, knowledgeable in English so we have to write in the local language which they can understand.

The following is one excerpt from a clinician who is leading clinical studies using autologous

stem cells in spinal cord injury patients:

Well you have to split patients down the middle into 2 groups, into those who have some education and those who come from a certain background, who are able to understand the argument and almost all of them will understand that there are no guarantees and it is a trial and there's the other half who are not very educated but who probably have a little money to spend or who have gone to great lengths to acquire the money and they won't understand for them it's a treatment. It's a treatment, but having said that, there's a responsibility for the persons working with stem cells to tell the patients exactly what they are buying which doesn't always happen. I mean I have patients coming in for second, third attempts after stem cell injections elsewhere.

Second, while patients may give informed consent, clinicians expressed concern that patients may be desperate for treatment and agree to participate in unsafe studies. The following is taken from an interview with two researchers and a clinician from Stempeutics who are discussing their views on private firms that provide untested, unpublished stem cell therapies.

X18: Half of the people do it though it is unregulated, but it's still not in unlawful and until it's made unlawful, they won't stop.

X19: And most of the patients, when they go there, they are very desperate, there they don't have any other resort left....

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X17: They prey on the hope of the people, most unethical.

The ICMR guidelines provide recommendations for obtaining informed consent in stem cell

research. Below are two sections that offer recommendations on how to address this issue:

Section 6.2.1 Restricted areas of research

Informed consent procedure for donation of ova, sperm, somatic cell or other cell types as detailed in these guidelines would need to be followed.

Section 8.0 Research using fetal stem cells and placenta

Informed consent to have a termination of pregnancy and the donation of fetal material for purpose of research or therapy should be taken separately.

The Department of Biotechnology has published General Considerations in the Process of

Obtaining Informed Consent for Individuals or Couples Who Will Participate in Stem Cell

Research [93] and includes the following considerations:

The informed consent process should disclose (I) possible risks from the procedure to obtain stem cells and how the risks will be minimized, (ii) the actions to be taken to protect privacy and confidentiality of the donors, (iii) the right to withdrawal from the study even after providing initial consent and the right to order destruction of tissues, cells and their derivatives, provided that the these samples can be linked to the donor at the stage when their destruction is sought.

The concern that patients are desperately seeking treatment for neurodegenerative disease raises

ethical questions for researchers. To address these issues, researchers reported interaction with

the institutional ethics board and with government agencies when applying for funding.

Government support requires adherence to these guidelines and ensure publically funded

institutions follow current guidelines.

3.2.6.3 Data Sharing

The final ethical concern raised by stakeholders is the limited data sharing in NeuroRM clinical

studies. Researchers and clinicians have reported that institutions that do not adhere to these

recommendations act unethically in not disclosing data from unsuccessful studies. One

researcher/clinician working on clinical studies involving stem cells discussed the lack of data

sharing within India concerning stem cell research:

44

Yeah, the whole thing, everyone you know is, I call it closet research, everybody's doing it in secret. Doesn't make sense, research is not meant for that, research has got to be shared got to be open and nobody wants to talk about what they are doing….

The previous section has discussed the ethical concerns raised during clinical translation. To

address these issues, the Government of India has drafted guidelines. In the next section,

regulation in clinical translation is discussed. First government agencies involved in this process

are presented and described. Next, the role of government regulations is grouped into two

categories, funding as well as research oversight and regulation

3.3 Regulation in clinical translation

3.3.1 Government Agencies

The four agencies involved in NeuroRM regulation, oversight and/or funding are the Indian

Council of Medical Research (ICMR), the Department of Science and Technology (DST),

Department of Biotechnology (DBT) and the Council of Scientific and Industrial Research

(CSIR). The mandate of each agency and their role in fostering translation are outlined.

The Indian Council of Medical Research (ICMR) [94] is situated within the Department of

Health Research, Ministry of Health & Family Welfare. It is responsible for policy development,

research coordination and promotion of medical research. Research priorities include control of

communicable diseases, maternal and child health, non-communicable diseases and mental

health. By achieving these priorities, the ICMR strives to reduce the total burden of disease and

to promote health and well being of the population.

The Department of Biotechnology (DBT) is located within the Ministry of Science and

Technology and promotes large-scale uses of biotechnology and support for research and

development related to manufacturing in Biology. The DBT fosters university and industry

interaction and identifies Centres of Excellence for research and development.

The Department of Science and Technology (DST) [95] is a subsection of the Ministry of

Science and Technology. It is responsible for the formulation of S&T policies and their

identification, implementation, and promotion of thrust areas of research in different sectors of

S&T. The DST provides support to basic and applied research institutions, supports technology

development and commercialization.

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The Council of Scientific and Industrial Research (CSIR) [96] is an ensemble of 37 research

institutions and is overseen by the Ministry of Scientific and Industrial Research. The council

provides support for scientific industrial research to maximizes economic, environmental and

societal benefits for the people of India.

3.3.2 Funding for basic science research

The government funds preclinical research through grants to research groups and through

investment in the creation of research centres focused on regenerative medicine innovation.

According to the Department of Biotechnology Annual Report 2009-2010, 53,443,600 Rest

($1,183,41.30 Canadian) were dedicated to stem cell research in 2009 [97]. This funding was

allocated to several research institutions to develop isolation, expansion and storage protocols for

adult stem cells. One researcher with LV Prasad discussed her experience with government

funding agencies:

So like that, we have various funding agencies like ICMR, DST, Department of Science and Technology, CSIR,… now it is easy for us to get grants, see if you submit a proposal and the proposal is convincing enough, we definitely get a lot of funding from Indian agencies

Table 3.1 Shows which institutions visited are receiving government funds, which agencies are

involved, what projects are funded and for what indication. The agencies cited related only to the

projects of stakeholders interviewed in this study. For example, the All India Institute of Medical

Sciences (AIIMS) study on Parkinsonism is funded through the Department of Science and

Technology (DST).

Table 3-1 Funding sources

Institution Funding Agency Approach Condition of Interest LVPEI DBT, Autologous SC Corneal damage NIMHANS DST, DBT, ICMR Multiple Motor Neuron

Disease AIIMS DST Autologous SC Parkinson’s Disease NCRM DBT Autologous SC Corneal damage NCBS DEA*, DBT, DST Auto/ Embryo SC Multiple

* Department of Atomic Energy

The government is expanding existing institutions and creating new research centres dedicated to

regenerative medicine research. Below are excerpts from two different interviews. In the first, a

46

clinician working within NIMHANS is outlining how his clinical research is funded. In the

second, a clinician supervising trials of stem cell use in a public hospital discusses the

government’s allocation of funds:

Well the government funds the academic institution [MM: Oh I see, so indirectly], it’s. The government covers the expenses. The city government, local population, runs the hospital. So they will not actually be giving to the patient, but they take care of everything. So indirectly government pays for it.

_ _

They do provide funding … but also the government doesn't support anybody because the facility that was established at CMC Vellore was done with the government so they choose whom they want to support and their priorities are different…. They've established some facilities I've told you in AIIMS which they are supporting. So I think the government is treading cautiously, probably, they just don't want to put all their eggs in one basket. So they just want to see whether the one in AIIMS is doing well. If it's doing well, probably they will give funding to other organizations as well, we don't know.

The Department of Biotechnology allocates funds to create new labs focused on RM research,

which house NeuroRM projects. One example of this is the creation of a Stem Cell Facility

within the All Indian Institute of Medical Sciences (AIIMS) in 2005 [98]. Currently, both the

Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR) support

projects therein. Table 3.2 presents NeuroRM research within the institution.

Table 3-2 AIIMS Stem Cell Facility Projects

Project Title Funding Agency

1. Culture of limbal stem cell for ocular surface reconstruction in stem cell deficiency disorder

DBT 2. To study the role of bone marrow derived pluripotent cells in peripheral

nerve repair in adult rats 3. Effect of bone marrow stromal cells transplantation and magnetic

stimulation in the sensory motor functional recovery of spinalised rats 4. Intra-arterial Autologous bone marrow MNC infusion in patients with

non progressive (static) encephalopathy with special reference to cerebral palsy

ICMR

Subsequently, this centre was designated a DBT centre of excellence for translational research

and has received funds through this program. The DBT Centres of Excellence program seeks to

strengthen institutional research capacity in identified areas of biotechnology through

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development of new research centres. These institutions have “a specific thematic focus but

having a multi-disciplinary approach for research in the specific theme” [99].

The Department of Science and Technology funds for generation of new facilities such as the

stem cell facilities at Christian Medical College in Vellore, India. The following is taken from a

statement from the Department of Biotechnology [100]:

In order to formulate road map in the area of stem cell research, a series of disease specific meetings were organized. Based on the consensus, road map for stem cell research has been categorized into basic research, translational research; human resource development; creation of infrastructure facilities; establishment of Centre of Excellence, institutions, creation of basic research units in medical institutions, good animal models for the diseases, etc.

This excerpt also discusses the role of government agencies in setting good practices through

regulations and oversight. The government is supporting consensus-building initiatives to

identify promising areas of research and allocate funds accordingly.

3.3.3 Regulation and oversight in NeuroRM translation

The Indian Council for Medical Research Guidelines for Stem Cell Research and Therapy

provide researchers and clinicians with recommendations for conducting research and clinical

studies using stem cells [101]. Stem Cell research is grouped into three categories; permissive,

restricted and prohibited. Each category imposes different requirements on researchers. The

Guidelines recommend the formation of a National Apex Committee for Stem Cell Research and

Therapy (NAC-SCRT) to review all stem cell protocols within the country. Any institutions

involved in stem cell research must have an Institutional Committee for Stem Cell Research

Stem Cell Research and Therapy (IC-SCRT) oversight to review studies as well. The

institutional committee includes clinicians, researchers and ethicists and reviews research

involving stem cells. While institutional review committees have been formed, the national

committee has not been assembled. One researcher who is using autologous stem cells in clinical

trials for motor neuron disease reported the following:

What they do say is you have to form an institutional stem cell, you know, like group [M: an institutional stem cell committee]. Yeah…but they also say you have to get approval of the national apex committee which doesn't exist…. So under the guidelines say you

48

should make an institutional committee. Then they say this committee should be registered with an Apex body, but there is no Apex body. So we write to them, there is no one. I understand from the meeting [with ICMR], we made this point. You know we say, you made guidelines, but you can't implement those guidelines.

Respondents from Stempeutics discussed their experiences in submitting stem cell protocols to

the government. While there is no formal body in place to review and approve of these

applications, the firm forwards their protocols to the ICMR regardless:

What we are doing has been cleared from our ICSCR committee and ethics committee and inform the ICMR, there is no national one formed yet, we just inform the ICMR…. .

While ICMR policy on stem cell research provides researchers and clinicians with

recommendations for work with stem cells, law does not enforce these. Participants report that

government awards require recipients to follow established good practices. This ensures that

government policies are followed until guidelines are enacted into law. According to one

recipient who has received DBT funds for embryonic stem cell research:

So you know, on the one hand you can have a lot of regulations, on the other hand you can have, some isolated places, … there may be some unscrupulous practices, say with the stem cells and since it is a huge country, very difficult to govern each and every person but at least the institutions that receives a government grant, can regulate them.

Scientists with the Nichi-In Centre for Regenerative Medicine discusses enforcement of

guidelines when applying for government grants below:

CE: You said there are guidelines, but I guess it is very similar to how it works in Canada, we also have policy statements on ethics, it's not law, you know. If you're publicly funded you should stick with those you should follow them or otherwise we can remove your funding but it is not a legal document [X1: exactly, exactly] and I guess it functions the same way here.

X1: Same, way, same way.

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3.4 Collaboration in clinical translation

3.4.1 Scientist – Scientist Collaborations

Collaborations between researchers are forming new partnerships through shared attendance at

conferences, through publications in their field. Collaboration provides researchers with the

expertise needed to transition existing research projects into NeuroRM studies. These

partnerships may involve sharing of materials, protocols, personnel and/or expertise. According

to one interviewee conducting research with NIMHANS:

You need a certain expertise which we lack and you find the person and say we'd like to try this out or it is that they are people that you know or work in the area, you chat and say why don't we try this….

One LV Prasad scientists spoke about her collaborations with the National Centre for Biological

Sciences and how this has furthered research on corneal stem cell research:

MM: Which animal models are best for this?

X8: So this is a rat model, and this is in another centre, we don't have it here, because it's just there's too many things, that one cannot do everything here and we don't have an animal house, so there's another centre in Manesar, National Brain Research Centre…they have the expertise. He has experience [using] many types of retinal cells, ganglion cells, he knows how to put the cells there and the cells of interest I have with me and I know how to sort them out. So we are trying to this with them.

One researcher with NIMHANS discussed his collaboration with NCBS, in which material and

knowledge are being exchanged:

This project I have undertaken in collaboration with [MM: national centre for biological sciences] yes. So [they are] developing various cell lines you know, from the transgenic mice models and also he has got various cell lines with the GFP, the green fluorescent protein. So the cell lines with this GFP, one advantage is that you can see the cell lines, if you transplant them into the brain using animal models, you will be able to visualize them. And also, you can monitor the cells, the transplanted grafts and also you can, you know, design appropriate experiments and study them, study the animal models. So now luckily we have got an animal model with hippocampus damage.

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3.4.2 Scientist – Clinician Collaboration

Section 4.2.3 presented data on the role of clinicians in translation, shows that physicians partner

with scientists to conduct clinical studies. Scientists in this study, who no not collaborate with

physicians, believe that their research is too early in development to warrant partnering with

clinicians. This is the experience of one NIMHANS scientist, highlighted below:

I never really thought, to be frank, I didn't get any chance to work with others who, you know, like say for example, any other transplantation group work who are already looking into the neural replacement and what is their success story…. I think in the next phase of our study, you know, I am planning to have some interactions….We have come to a stage now that we can now think of our new projects and to look into a different way, to look into different more practical approaches. See it should be more translational to human studies. I think that now we have come to that stage actually. I have a lot more interaction with the people who are working in this area and I sort of discuss with them and have a project with them… clinicians and even the basic scientists working in this area

In two interviews, one at NIMHANS and AIIMS, we interviewed researchers who are partnering

with physicians on clinical studies. They stated that institutions with both clinical and research

departments foster these partnerships. Below are two interview excerpts, one from each

interview discussing collaboration in these institutions:

I'd say the people who made NIMHANS a reality, they thought that you know, along with the clinical disciplines we have to have basic science research institutes too because it was recognized that brain, by itself, brain was and going to be a black box for quite a number of years and people didn't realize, you know, if you wanted to have effective treatment for any of these complex neurological illnesses you have to understand more about the biology …. When a psychiatric patient comes for treatment at NIMHANS, you know, he is looked at by a team consisting of psychiatrists, clinical psychologists, psychiatric social work[ers]

- -

MM: Now, with this trial, where is this work actually undertaken? Is this all done at AIIMS or is this done in collaboration with physicians outside?

X16: The patient, the surgery and the assessment will be done at AIIMS, the isolation of the cells will also be done at AIIMS, but the stem cell multiplication and culturing will be done in a lab in Mumbai.

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3.4.3 Clinician-Clinician Collaboration

Clinicians were asked if they had partnered with colleagues on NeuroRM studies. There were no

reported collaborations between physicians that we engaged. Given the recent emergence of

NeuroRM clinical trials, participants reported there is limited opportunities for partnering.

According to one spinal surgeon who has conducted stem cell trials for spinal cord injury:

...I am a neurosurgeon, I am involved with the clinical end of it. Much of the communication that is happening is related to the basic science issue, aspects of this which is really out of my area …. But as far as the clinical end of it is concerned, it's not a matter for discussion on a daily basis, it's something where trends emerge after many years or months and over many dozens of patients.

Despite the lack of collaboration, participants believe these partnerships will be important in

clinical translation of NeuroRM. Pooling data from multiple sources will allow for

standardization of good practices according to our interviewees. This is reflected in the interview

below with one surgeon conducting stem cell clinical trials for spinal cord injury:

Once we get good results and substantial good data to back it up, not only my studies we have a few other doctors in Chennai who are doing a lot of stem cells, so once we get everybody's data together and we sit and analyze each and everyone's data, we… are able to categorize and then we will be in a better position... The only thing is we need more of, there are few other hospitals who have a huge number of data, mine is comparatively less because I'm still very apprehensive. I want to see a few results before I take a bigger step and start accepting more patients so.

This section discussed researcher and clinician collaborations within India. Partnerships among

scientists, clinicians and between clinicians and scientists have been presented. Next,

partnerships with international collaborators are presented.

3.4.4 International Collaborations

International partnerships involved the exchange of knowledge exchanges and materials.

Furthermore, participants spoke about cultural differences between nations and how different

perspectives on NeuroRM technologies influence how partnerships are formed. International

partners exchange knowledge between research groups. This is exemplified in the case of the

Nichi-In Centre for Regenerative Medicine’s involvement with the Training Program In

Regenerative Medicine (TPRM) based within the University Health Network in Toronto,

Ontario. Faculty from the University of Toronto and Nichi-In have exchanged students and had

52

visiting faculty members speak within each institution. In the following excerpt, one interviewee

with the Nichi-In Centre for Regenerative Medicine discussed how his collaboration with the

University of Toronto was initiated:

MM: I had a question, just regarding…your collaboration with the training program, I was wondering how that came about?

X1: …. Earlier before this, in 2004 I have visited the laboratory [in Toronto].....They had published in Science at that time…on epithelium for retinal stem cells things like that. So they gave the protocol to us and reproduced the same in India. Then we wanted to take to [this into] clinical application…. We had a teleconference. We had a personal visit, we started it.

Scientists with a private firm discussed how international collaboration impacts basic research

development:

MM: So you work with hospitals within India, that you collaborate with, I know I read you have collaborations with internationally, within Canada…. When you work with partners overseas what is your role in those?

X19: Now we are not working in the international collaboration for clinical purpose, we only collaborate for basic research… our scientists go there for, do work with them…They come to our labs to try some of their work…[and] exchange of ideas.

We also spoke with one researcher who is collaborating with scientists an international partner

on scaffold and limbal stem cell therapy research. Researchers within India have developed a

protocol for culturing retinal stromal cells on an amniotic membrane. Researchers at the

partnering institution overseas generated novel scaffold composites that can support cell growth.

These scaffolds were combined with limbal stem cells cultured and implanted using approach

developed in India. In our interview, the partner located in India discussed how this

collaboration began , the course of the partnership and outcomes of this arrangement. In the

excerpt below, the collaborator is identified as M:

One of my students who actually worked with me on this project had moved to another centre…wound up in M's lab, … Then she mentioned to M, that I am coming there then M got in touch with me, she says why don't you come down and give a talk there so I went…. One of the things is, we use human amniotic membrane as a carrier for our cells. whereas M works on a biocompatible substrate. She has a substrate….[made] through cell lines, not primary human tissue. Where as we knew how to grow human cells, she didn't have much experience with primary human tissues…. She sent me the substrate and that was a transparent collagen, so we grew those cells on that [substrate] and then she characterized the materials and we grew the cells and showed that they make very good

53

adhesions…. that's when, then that paper got published and we are very happy about that.

3.4.4.1 Cultural considerations in International Collaboration

Clinicians face skepticism from researchers in the West surrounding NeuroRM clinical studies in

India. Interviewees cite that limited amount of quantitative data prevents publication and

acceptance of clinical reports overseas. This is reflected in the quotation below from one

clinician with NCRM discussed challenges in collecting quantitative data and how this impedes

acceptance in international journals:

Anyone who is asking me, why do you say this patient has improved and the answer is, I could tell them that the patient says that he has improved and there is nothing more that I can tell them. So, no journal will accept that. So yes, there is a science to it but we are unable to do the science the way it should be done because of a lot of factors, patient compliance being one of the factors.

Indian interviewees have reported greater ease when partnering with Eastern nations such as

China due to shared cultural values and understandings. The quotation below is taken from one

researcher concerning initiation of international collaborations:

X9: ...We saw the results from, so we really have a little more respect for the Chinese and Koreans … than for Western countries, because we all come from the orient. So if I see the work of a Chinese person I respect it just as much as if they were from somebody from the United States. The Western world doesn't, they obviously think, think that anyone that comes from Asia is suspect, not just the data but everything also. I've been to China and I've met those guys and you know I've seen those patients, I've seen, they are doing a great job.

MM: Does that make you want to work more or collaborate within China with Asia than with the West.

X9: Right I would be happy to collaborate with China because you know we understand each other. There is more, in Chinese and Indian and oriental, there's a little concept of holistic healing. Healing is important, it's like a cultural spiritual thing and stem cells are about healing…. So I would be happier to collaborate within Asia.

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3.5 Conclusion

Stakeholders involved in NeuroRM translation and roles of each were identified. The role of

government bodies in providing funding, governance and collaboration facilitation has been

reviewed. Finally, the impact of collaboration in this process has been outlined, with cases of

national and international partnerships enumerated. This data has been collected to address the

three objectives of this research:

1. To identify the stakeholders involved in translation, roles of each in clinical translation

and challenges faced by each group during translation.

2. To describe India’s regulatory environment concerning NeuroRM translation by


3. To determine the role of collaboration in clinical translation by mapping where

partnerships develop and studying how these impact translation.

Chapter 5 discusses the findings of this study in order to address the overarching question “What

are the challenges to translation of NeuroRM in India?” Recommendations based on the

experiences of stakeholders are presented.

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Chapter 4 Discussion and Conclusion

4.1 Introduction

This research has presented data on the current state of neuroregenerative medicine translation in

India. This chapter will discuss the results of this research. Key findings will be summarized

(Section 5.2) and recommendations to foster translation are outlined (Section 5.3). This is

followed by a discussion of future directions (Section 5.4) and conclusions (Section 5.5).

4.2 Summary of Findings

This study has determined barriers to translation of NeuroRM within India and how these are

being addressed. Three objectives were put forward to address this question. The findings of this

work are summarized here and grouped according to these objectives.

4.2.1 Objective 1: Identify stakeholders involved in translation, roles of each in clinical translation and challenges faced by each group during translation.

Researchers, clinicians, policy makers and private firms are translating NeuroRM research. Basic

research is divided into two categories: 1) Characterization studies that explore mechanisms of

NeuroRM approaches and 2) Protocol development studies in which technologies, viewed as

proven for other indications, are adapted for novel indications. Researchers are entering this field

from other areas of interest in neurobiology. This transition is catalyzed by partnerships with

colleagues in other fields. Government support through initiatives such as the Department of

Biotechnology Centres of Excellence Program assists Indian scientists in applying existing

knowledge and materials in this emerging field. While government support is available for

researchers, assistance for clinical development is limited.

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Clinicians are leading clinical studies with NeuroRM technologies through collaborations with

researchers. Clinicians interviewed in this research are situated within 1) Institutions with both

basic science and clinical departments or 2) Independent hospitals. Stempeutics and the Nichi-in

Centre for Regenerative Medicine are two centres offering stem cell materials for clinical

application. These firms work with doctors situated within independent institutions on small-

scale clinical studies. Clinicians report a lack of communication between clinical trial leaders,

which creates difficulties in determining the safety and efficacy of NeuroRM interventions

across studies. Limited quantitative outcome measurements and loss of patients to follow up

hinder translation by preventing collection of data on safety and efficacy of NeuroRM treatments

using quantitative outcomes. Subsequently, this creates difficulties when trying to publish

findings in international journals generating skepticism in potential partners overseas.

Preclinical studies in private firms are grouped into two categories: 1) Adaptation studies which

apply existing treatments for neurodegenerative indications. 2) Characterization studies research

to determine efficacious cell types, dosages and delivery strategies. The process for receiving

approval for commercial products was presented. In addition to current requirements on stem cell

research, private firms must receive approval of the Drug Controller General of India to

commercialize. The Nichi-In for Regenerative Medicine and Stempeutics provide cell expansion

services for patients while Reliance Life Sciences has developed ReliNethra ©, an autologous

bio-engineered composite limbal epithelial graft for corneal disorders .

4.2.2 Objective 2: Describe India’s regulatory environment concerning NeuroRM translation by determining which agencies are involved and their role in clinical translation.

Government agencies involved in NeuroRM translation are the Indian Council of Medical

Research, Department of Biotechnology, Council for Scientific and Industrial Research and Drug

Controller General of India. Government agencies support translation in three ways 1) funding 2)

regulation/oversight 3) collaboration development. The government allocates funds to assist

existing research groups in expanding their research into NeuroRM studies. The government has

funded the creation of new facilities dedicated to Regenerative Medicine such as the Stem Cell

Facility at the All India Institute of Medical Sciences. Regulations, such as the ICMR guidelines

for Stem Cell Research and Therapy, provide scientists and clinicians with recommendations on

57

good practices. While guidelines are not enforced by law, researchers are required to adhere to

these guidelines in order to receive government grants. As these guidelines are not binding by

law, firms offering treatments without government approval continue to operate in the country.

As patient are paying out of pocket for treatment, firms are not applying for government grants

and are not required to adhere to government policies. This raises ethical concerns surrounding

patient exploitation, both of Indian and international patients.

4.2.3 Objective 3: Determine the role of collaboration in clinical translation by mapping where partnerships develop and studying how these impact translation

Researchers are partnering within India and with international collaborators on preclinical

studies. Collaborations between scientists are forming through; shared attendance at conferences,

existing collaborations, government matching and independent seeking out of partners.

Scientists-clinician partnerships are facilitating clinical trials of new technologies. These

partnerships form within institutions with clinical and research departments or through

independent partnerships between a physician and private firm. Clinician-clinician collaboration

is seen as important in establishing safety and efficacy of NeuroRM treatments, however these

partnerships are absent. The government fosters collaboration through the creation of research

centres, which house multiple research and clinical teams; through networking events that bring

stakeholders together and by directly linking researchers. The creation of new dedicated research

departments or institutions such as CMC Vellore is also fostering translation.

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4.3 Recommendations for nations seeking to translate in NeuroRM

4.3.1 Build capacity in NeuroRM research through investment in expansion of existing research facilities

Basic research moves forward by researchers and clinicians that adapt existing resources in

emerging NeuroRM studies. Previous work has shown that India is building capacity in

regenerative medicine to address local health needs through investments in existing research

institutions [102]. NeuroRM translation follows this trend as researchers branch into this field

from related projects. Nations seeking to innovate in NeuroRM can foster translation by

identifying centres where this expansion takes place and provide funds to adapt existing

technology in NeuroRM studies. Translation is also taking place within new facilities that are

added to existing institutions. Stem Cell Facilities at the All India Institute of Medical Sciences

and Christian Medical College exemplify this approach. Nations can promote translation by

identifying leading centres in this field and by supporting stakeholders seeking to enter into this

field.

Based on the institutions interviewed in this study, governments can provide support in one of

two ways: 1) by funding for new facilities and 2) supporting collaboration building between

research institutions.

4.3.2 Consensus building in setting preclinical research goals

Consensus building between scientists is recommended in order to standardize good research

practices and setting a national research agenda. Although the Indian Government has organized

consensus-building workshops in order to set research priorities (Section 4.3.2), participants are

still divided on the current state of NeuroRM. One group believes knowledge of NeuroRM is

limited (Characterization Studies (Section 4.2.2.1)) while others argue that there is sufficient

existing knowledge to begin clinical trials (Protocol Development studies (Section 4.2.2.2)). .

Consensus building initiatives for stem cell research have helped scientists in setting research

priorities, identifying challenges and determining best practices in other nations. The European

Society of Cardiology assembled a task force to [103] to investigate the current state of

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progenitor/stem cell therapy in the treatment of cardiovascular disease. In 2010, the International

Mesenchymal Stem Cell Therapy (MSCT) Study Group published findings of a consensus

meeting to share evidence concerning the use of stem cells to treat multiple sclerosis [104].

Policy makers can foster translation by promoting consensus building between scientists and

policy makers take place to determine what current state of NeuroRM knowledge. A harmonized

national policy can unify researchers by recommending needed research and allocating funds

accordingly.

4.3.3 Standardization of outcome measures in clinical trials

Clinical trials that rely on qualitative outcome measures are met with skepticism according to

clinicians interviewed in this study. The barriers to obtaining quantitative outcomes in NeuroRM

trials in India are limiting funding and equipment as well as loss of patients to follow up. Trials

that rely on qualitative outcomes are published less frequently than quantitative measures.

Qualitative trials with negative outcomes are published less than those with positive outcomes

(Stern et al (1997))[105]. NeuroRM clinicians face these challenges, either having studies

rejected or reporting that colleagues with unsuccessful trials are not publishing findings. It is

recommended that NeuroRM clinical trials incorporate both qualitative and quantitative

measures. Qualitative measurements have been increasingly used in clinical trials as physicians

place more importance on reported experiences of patients in trials. One example is the Patient-

Reported Outcomes Measure Information System (PROMIS) initiative developed by the

National Institutes of Health [106]. This combines patient reported outcomes with quantitative

measures for trials. Clinical trials for neurodegenerative diseases are following this trend. Studies

on qualitative outcome measures in dementia put forward the importance of understanding

patient’s experiences and perceived changes during clinical trials [107 -109].

Neurodegenerative diseases not only impair biological processes but also have lasting impacts on

a patient cognition, and memory. Likewise, spinal cord injury clinical trials are incorporating

qualitative measures to measure clinical outcomes as reflected by recent guidelines from the

International Campaign for Cures of spinal cord injury Paralysis (ICCP) Clinical Guidelines

Panel [110]. It is recommended that funds for equipment to perform quantitative measures and

transportation to bring patients in for follow up be incorporated into clinical study submissions.

Given that neurodegeneration impacts patient mobility, cognition and memory, understanding

60

perceived changes during clinical trials, in combination with quantitative measures, are

important in moving NeuroRM translation forward.

Improving post intervention observation is critical in determining the safety and efficacy of

NeuroRM. Loss of patients to follow up is a recurring challenge in clinical studies [110-112].

NeuroRM translation faces a distinct challenge in that many conditions patients seek treatment

for also impair there ability to access treatments. This refers to reduced mobility that impedes

travel as well as impeded memory and vision which create additional challenges in returning for

consultation. Furthermore, research and clinical activities are located within large urban centres,

however, study participants are travelling great distances to receive initial treatments but fail to

return for observation. It is recommended that measures be implemented to select for patients

who are able to complete studies, who have access to transportation for regular treatment and

who are informed of all responsibilities before enrollment. Sprague et al, 2004 have outlined

steps for reducing patient loss to follow up that can be implemented before, during and after a

clinical trial. These are grouped into primary, secondary and tertiary interventions [113]:

Primary Intervention: Trial design should exclude individuals unlikely to complete the study and

inform participants of all potential risks and obligations of participating in the study

Secondary Intervention: Innovative designs to minimize losses during a trial should be

employed. These include regular contact with patients and reduce demands of participant by

combining tests within fewer visits

Tertiary interventions: Locating patients lost to follow up through contact with family physician

or family contact given by the patient.

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4.3.4 Government oversight of clinical trials of NeuroRM

This research indicates that oversight for NeuroRM clinical studies is still in development within

India. Previous research has discussed challenges in conducting clinical trials in India [111-114]

including limited regulatory oversight. According to the World Health Organization on clinical

trial ethics within India [115], a senior scientist with the Indian Council of Medical Research

(ICMR) highlights the need for oversight of clinical trials:

Unless we put in place systems that ensure safety of patients and good quality of trials, people will get away with whatever they can get away with

Unregulated use of RM technologies marketed as cures profits on the hope of patients faced with

debilitating and long-term conditions. Currently, the ICMR Clinical Trials Registry - India

(CTRI) is in place to foster transparency and minimize duplication of clinical studies within the

country. Recent studies by Tharyan (2009) and Pandey et al (2009) [116, 117] suggest the CTRI

is improving clinical trial transparency within India. As NeuroRM translation takes place,

oversight is needed for clinical studies. This may be achieved through enforcement of existing

recommendations such as the International Society for Stem Cell Research Guidelines on Stem

Cell Translation [118] and the Indian Council of Medical Research Guidelines on Stem Cell

Research [119]. Furthermore, increased communication between clinical trial leaders may

promote transparency by having all findings from clinical trials made available to the public.

Policies that reward studies with transparency integrated into trial design can further promote

transparency and assist in oversight of clinical studies.

Further questions should be explored in developing harmonized guidelines for clinical trials.

Currently, clinicians reported involvement in clinical trials where participants do not pay to

receive the intervention. Others reported that “experimental treatments” were offered and

patients charged a fee for the service. The offering of experimental treatments for profit raises

ethical challenges that must be discussed. Within the confines of this research, scientists and

clinicians who charge patients respond that sufficient knowledge is available to justify this

practice. Conversely, other stakeholders indicated that charging for these interventions preys on

the desperation of patients as outlined in section 3.6.2. Next steps may include establishing

dialogues with patients to identify what is acceptable risk and ensuring informed consent is

given.

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4.3.5 Support for Collaborations to Catalyze NeuroRM Translation

This study has identified collaborations at each stage of NeuroRM translation and determined the

impact of each in moving research forward. National and international collaboration between

scientists generates new projects and expansion of current studies into NeuroRM research.

Partnerships generate new knowledge and build capacity in an emerging field [120, 121].

Likewise, research on international collaborations concerning health biotechnologies has shown

that partnerships benefit developing world partners by providing strategic regulatory, financial

and scientific knowledge [122]. This study has identified where collaborations are promoting

translation and presents instances where no collaboration is taking place, slowing clinical

translation. The following are key points concerning collaboration in translation of NeuroRM

1. Physician-researcher partnerships are critical when conducting clinical trials

2. Limited clinician-clinician partnerships hinder protocol development

3. Government intervention is important in establishing partnerships between stakeholders

Clinician-researcher partnerships can be developed through the creation of research centres with

clinical departments within them. Alternatively, expansion of clinical departments within

research institutions will connect stakeholders and foster translation. Between clinicians,

networking events would promote standardization and harmonization of practices. Additionally,

support and oversight from the government for multi-hospital clinical trials would connect

principle investigators and facilitate collaboration. One example of this is the Canadian

Networks of Centres of Excellence Program, which has three objectives according to a 2009

evaluation report issued by the Government of Canada[123]:

1. Facilitate the creation of networks on a national and an international level;

2. Support networking activities among well-established researchers or research teams to

encourage them to develop new partnerships with receptor communities

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3. Respond to the needs of both researchers and receptor communities for interaction,

partnership, and networking.

This initiative is effectively building interdisciplinary partnerships between institutions. Non-

Governmental Organizations, scientists and clinicians reported increased collaboration due to

this initiative. Limitations of this approach include turnover of project leadership and short time

frames allowed to generate results. Application of a similar model in India for NeuroRM may

foster collaborations that will foster translation.

4.4 Future Research

Two areas that warrant further investigation are introduced in this section. 1) Discussing impacts

of culture on NeuroRM and how this impacts translation, 2) Medical tourism and NeuroRM

translation and 3) NeuroRM Patenting. These were introduced by interviewees however I have

concluded that there was insufficient data to explore these topics within this project. They were

highlighted by several participants however the discussions, on review of the data, were based on

opinion of participants rather than on personal experience.

4.4.1 Discussing impacts of culture on Neuro RM Translation

Questions concerning public perceptions of NeuroRM were not explored in this study as the

focus was on the stakeholders involved in developing NeuroRM. Sections 4.1.3 and Section

4.4.4.1 introduced the role of culture in NeuroRM translation. Section 4.1.3 outlined growing

demand for NeuroRM treatments in rural areas due to patients living alone as children move into

large cities. Section 4.4.4.1 looked at the role of different perceptions of NeuroRM technologies

of Indian researchers and overseas scientists and how this impacts collaboration. In this study,

two researchers discussed how traditional healthcare practices inform public perceptions of

NeuroRM. One interviewee describes the traditional health practices, specifically Ayurveda, that

may impact public perceptions of NeuroRM:

MM: You mentioned the Ayurvedic medicine; I'd like to ask if you think it's because of existing cultural or religious beliefs in Ayurveda that people are willing to try regenerative medicine?

X14: Yes I would think that, the idea of regeneration or rejuvenation is a better word is probably there to a large extent but again that is confined to a certain segment of the population, not everybody, but if you looked at rural India, then the type there, there are

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many, many different types of indigenous medicines, there's you have the homeopathy, all of them and many of these are recognized as official forms of medicine.... So that sort of idea [is] there….

Studies have looked at the impact of public perceptions of stem cell research in the developed

world [120]. The public is skeptical of advances in stem cells, particularly within private firms

[121]. This study indicates that the Indian public may be willing to explore technologies due to

existing cultural perceptions of health, such as Ayurvedic Medicine. The view that illness

originates due to imbalances is connected to the goal of regenerative medicine to restore

damaged or lost materials. Ayurveda is [122]:

One of the world's oldest medical systems. It originated in India and has evolved there over thousands of years. The aim of Ayurvedic medicine is to integrate and balance the body, mind, and spirit. This is believed to help prevent illness and promote wellness. Ayurvedic medicine uses a variety of products and techniques to cleanse the body and restore balance.

Additionally, the idea that different approaches to healthcare provision impact how these

treatments are received emerged in one interview that discussed how India’s privatized

healthcare system supports development of private firms:

The corporate medical establishment is all about turnover and revenue. So it's about offering patients a kind of treatment where you come in and you have the treatment, you pay your package money and you go away.

Previous research indicates that cultural perceptions of new technologies influences how an

emerging field is funded and taken up by the public [123]. While this is an important

consideration when looking at translation, studying these cultural determinants requires

engagement with the public and patients who have received NeuroRM treatment. This is outside

the scope of this work but is recommended in future research

4.4.2 Medical Tourism and NeuroRM Translation

Medical Tourism refers to the flow of citizens of developed nations to developing areas of the

world to receive medical care [123]. Physicians in developed nations are concerned that

treatments offered by tourism firms, including stem cell treatments, are unsafe [124 -132].

Developed nations express concern that private firms are preying on desperate patients by

advertising cures for debilitating diseases. Most recently, the recent outbreak of multi-drug

resistant superbugs linked to Indian medical tourism has sparked debate over the risks of medical

65

tourism and generated public discussion of the dangers of travelling abroad for medical care.

[133-138]. In response to these concerns, the International Society for Stem Cell Research

(ISSCR) Guidelines for the Clinical Translation of Stem Cells has criticized the direct to patient

marketing of stem cell therapies as reflected in the excerpt below:

Numerous clinics around the world are exploiting patients’ hopes by purporting to offer new and effective stem cell therapies for seriously ill patients, typically for large sums of money and without credible scientific rationale, transparency, oversight, or patient protections. The ISSCR is deeply concerned about the potential physical, psychological, and financial harm to patients who pursue unproven stem cell-based “therapies” and the general lack of scientific transparency and professional accountability of those engaged in these activities.

While scientists and physicians in developed nations have spoken out against these practices,

limited research on the perspectives of providers in India has been published [139,140]. The

McLaughlin-Rotman Centre for Global Health has studied stem cell tourism from the perspective

of providers [141] and notes that differences in medical practices between societies impact

perceptions of stem cell treatment:

While Western medicine requires proof of safety and efficacy for invasive health interventions administered by health care professionals, this may not be required by all countries or for all cultures.

Research on NeuroRM medical tourism and impacts on translation from the perspective of

Indian providers would provide developed nations with information on the current state of

NeuroRM therapies offered within India. Section 4.6.2 focused on ethical issues emerging in

NeuroRM treatments including informed consent and patient exploitation. When asked about the

provision of unproven stem cell therapies to both national and international patients, all

participants expressed concern over limited enforcement of guidelines that has resulted in the

emergence of stem cell clinics offering therapy. This research identifies an emerging

regenerative medicine tourism sector within India for neurodegenerative medical diseases, and

recommends that exploration of its impact on translation within India be followed in future

studies.

66

4.4.3 Patenting and NeuroRM Translation

Patents of Regenerative medicine technologies create incentives for stakeholders to translate

[149-151]. In the United Kingdom, Rowely and Martin (2009) have shown that patents foster

translation from the bench to bedside. Rowely discusses the benefits of intellectual property

protection in incentivizing translation of regenerative medicine. In their report they highlight the

following:

Intellectual space and freedom to operate was identified as a concern that had the

potential to greatly hinder UK science and industry. The majority of respondents

mentioned difficulties associated with IP rights and freedom to operate in the intellectual

space.

This study has identified one patented product in section 3.2.5 however further data would be

needed to determine how patents impact translation. In this study, researchers were asked to

discuss the process of submitting applications for review and to reflect on interactions with

government agencies. Only one stakeholder commented on the current state of patenting and said

the following when asked about patenting preclinical research:

So right now, the Indian laws are very vague. Really they are not modified or modernized

at all, in relation to biological medicine.

Other stakeholders did not report any interaction with patent agencies at this stage of

development. Many stakeholders indicated that NeuroRM translation has only begun. Research

that tracks patenting in the future would identify the connection between translation and patents.

Based on research on patenting in other emerging fields, protecting intellectual property of

innovators in this field may catalyze translation.

67

Conclusion

This study has applied qualitative case study methods to understand NeuroRM clinical

translation, within its context. India has been chosen for this purpose, as it is one of the first

nations to translate in this field based on publications, patents and media reports. This study has

identified stakeholders involved in the translation of Neuro-Regenerative Medicine within India.

The roles of each grouping were enumerated, as were interaction between them. Contributing

factors and barriers to clinical development have been uncovered. Collaborations were tracked to

understand the role of partnerships in translation. Recommendations and future directions of the

field for others seeking to enter into NeuroRM studies have been put forward.

India is moving forward in this area by building on existing resources. This is reflected in the

development of commercial products and reported clinical trials. Communication between

clinicians, scientists and government agencies is integral to generating new ideas, translating

discoveries into clinical trials and ensuring good practices are followed. Enforcement of

guidelines through grants ensures good practices are followed, however, enactment of guidelines

into law is needed to ensure all institutions will follow accepted practices. Neurodegenerative

diseases are a distinct category of diseases that can impact mobility, cognition, vision and

emotional health. Accordingly, treatments for these conditions are currently in high demand as

reflected by the emergence of stem cell tourism. It is hoped that this study fosters discussion of

the current state of NeuroRM translation within India and globally.

68

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Appendices Appendix A: NeuroRM Study Outline

Neuroregenerative medicine in India: Regulation, Translation, and Collaboration

The prevalence of neurodegenerative disorders is increasing worldwide as are the associated economic and social costs. Concurrently, emerging economies, such as India, are witnessing unprecedented levels of economic growth and are investing heavily in research institutions, health centres [1] and in new areas of research such as Neuro-Regenerative Medicine [2] (NeuroRM). NeuroRM involves the repair, replacement or regeneration of cells, tissues or organs using technologies such as stem cell or gene therapy [3]. In terms of NeuroRM related publications, clinical trials and therapies offered [4], India is closing the gap with current leaders in this area such as Canada and the United States. What is not as apparent are the underlying processes that have resulted in this phenomenon. What policies support the development of these technologies, what are the challenges of conducting NeuroRM research and how are these overcome? As Indian firms move new interventions into the clinic, are they collaborating with partners in industrialized nations and if not, what are the barriers to building partnerships in this field? In this project, we ask how are scientists and clinicians, working in Neuro-Regenerative Medicine in India translating research into the clinic. We will be traveling to these institutions and engaging researchers in one hour interviews about these topics. What regulations govern this area and how are collaborations fostered in this field? It is important to address these questions for several reasons. Firstly, we will engage scientists and clinicians working in NeuroRM in order to determine what aspects of India’s regulatory environment are moving new interventions safely and quickly into the clinic and which are hindering this process. We will explore, with researchers, what institutions they interact with to receive funding approval, ethics oversight and government approval to carry out their research. Furthermore, many policies have recently been drafted and implemented such as the Indian Council for Medical Research’s Guidelines for Stem Cell Research and Therapy [5], which were drafted in 2006. By asking these individuals about their views on these policies and how they have impacted their work, we will generate recommendations, if needed, to inform policy makers of the needs of researchers and physicians as new policies are enacted. Secondly, emerging economies, such as India, are now carrying discoveries in NeuroRM from the research lab into the clinic, treating patients with interventions such as stem cells for conditions including spinal cord injury, Parkinson’s disease and Multiple Sclerosis. In carrying discoveries forward, researchers and physicians traditionally face many questions. How many animal models are needed and patient population should be chosen when conducting a trial? What ethical concerns are raised and what types of review are in place to guide this process? What regulatory agencies are involved in this process and what is their role? This work will provide individuals in India, who are seeking to conduct trials in the future, with a resource that will inform them of the requirements they must adhere to. For researchers in other nations, that have not generated therapies from NeuroRM research, these findings will inform policy makers of what policies can help in this transition. Finally, there is an increasing body of literature that has focused on the importance of

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international collaboration in the health biotechnology sector [6]. These partnerships, either between emerging economies or between emerging and industrial economies, frequently referred to as South-South and North-South collaborations have many benefits for both parties. Looking to South-South collaborations, these partnerships ensure that large-scale projects can meet the direct needs of each nation’s population. In North-South collaboration, Northern firms are able to access larger patient populations and face lower operating costs. Southern firms gain access to resources, such as funding, equipment, or training. We will ask researchers about their experiences collaborating within India and abroad. What do scientists, clinicians and policy makers believe is needed to foster collaboration in NeuroRM? What are the advantages of these partnerships and the barriers they faced in establishing them? By engaging individuals with experience working in this field, we anticipate that this work will highlight India’s achievements in both the basic sciences and clinical application of NeuroRM. Furthermore, this will be a valuable resource for both Indian researchers and potential collaborators overseas, as it will provide an overview of the range of work being undertaken, how clinical translation occurs and informs the broader scientific community of opportunities for collaboration in India. The ultimate objective of this work is to assist scientists, clinicians and policy makers working in NeuroRM internationally in their efforts of developing efficacious and safe therapies for neurodegenerative conditions and improvement of global health. Investigators Dr. Abdallah Daar, Dr. Claudia Emerson and MSc. Candidate Mark Messih are with the Regenerative Medicine Ethics Network (RMEthnet) and are funded by the Canadian Institutes of Health Research. We are based out of the McLaughlin Rotman Centre for Global Health at the University of Toronto. For more information on our network please visit (http://mrcglobal.org/projects/rmethnet). 1. Brain disease will be killer no. 1: Expert, in HindustanTimes.com, Dec. 17, 2006 2. Greenwood HL, Singer PA, Downey GP, Martin DK, Thorsteinsdóttir H, et al. Regenerative Medicine and the

Developing World PLoS Medicine Vol. 3, No. 9, e381 3. Daar A, Greenwood H. A proposed definition of regenerative medicine. Journal of Tissue Engineering and

Regenerative Medicine. Vol.1 No.3 179 - 184 4. Lander B, Thorsteinsdóttir H, Singer PA, Daar AS, Harnessing stem cells for health needs in India. Cell Stem

Cell (2008) 3: 11-5. 5. Indian Council of Medical Research. Stem Cell Guidelines

http://www.icmr.nic.in/stem_cell/stem_cell_guidelines.pd. Accessed on March 1, 2009 6. Thorsteinsdóttir H, Singer PA, Daar AS. Innovation Cultures in Developing Countries: The Case of Health

Biotechnology. Comparative Technology Transfer and Society – Vol 5, Number 2, August 2007, pp. 178-201

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Appendix B: NeuroRM Interview Guide 1. Background - Researchers

• What is the focus of your research? • What are the most treated neurological disorders in India? • What types of relevant research are underway at your institutions

2. Background - Clinicians • Tell me about your experience leading clinical trials. • What were selection criteria used? Why? • What were the observed outcomes? How were these measured? • What are challenges that develop when conducting clinical studies? • Personal experience of medical tourism, part of your practice? • Where are people coming from, numbers?

3. Regulatory agencies, laws and funding

• What agencies do you need approval from to move forward? • What are the major funding agencies? • Can you tell me about the interaction you have with government agencies in

this process? • Does the government promote partnerships in your experience? If so how?

4. Ethics

• Ethical challenges this type of research presents if any? • What are personal ethical challenges you face in this field? • How were these reviewed?

5. Collaboration

• Collaborations overseas? With whom? Why? What does (country x) bring to collaborations?

• Characteristics of collaborations, where is the trial done? which REB is applied to?

• How does the public perceive these therapies? How do patients learn about your work?

Conclusion

• Where do you foresee the field moving next? Advances in the next 5-10 years • Recommendations for improvements that can be made?

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Appendix C: NeuroRM : Generated Codes

Translation

Transition to NeuroRM Stakeholders discuss how they began work in NeuroRM from other areas of study

Access to RM therapies Related to future directions of NeuroRM, participants reflect on how accessible therapies can be in the future

Animal Models What are recurring animal models and justifications for selecting these models

Barriers to Translation Stakeholders asked to reflect on any barriers not discussed in the interview Challenges in Outcome Measurement Barriers to obtaining outcome measures

Characterization studies Instances of early preclinical studies

Clinical Challenges What are the perceived difficulties reported by trial leaders?

Commercial Potentials and outcomes

How basic scientists envision their work moving in terms of commercial application.

Commercialization Process Experiences of private firm stakeholders in developing a commercial product

Conditions Studied What is the focus of a clinician’s efforts, private firm’s target and/or a researchers preclinical model.

Designing Research Protocols Considerations when starting a new preclinical study, necessary resources, materials, regulations to consider

Implications of Qualitative Measurement

Qualitative reports are left unpublished, building skepticism in the international community

Materials and equipment Where are materials (referring to biological and equipment) coming from? How are they moved?

Measuring Neuro-regeneration How is growth measured in vitro? In vivo? What are reliable measures and challenges in this process?

NeuroRM Mechanisms NeuroRM technology studied (cell, scaffold etc.)

Patient Consultation How did participants come to learn about studies and what were they told of the trial beforehand?

Patient Expectations Clinicians report hopes expressed by patients (walking, restored sight, improved memory)

Patient Financing and Costs Sources of funds for paid experimental therapy

Patient Follow Up How is contact maintained with patients? If not, why are patients lost to follow up

Preclinical threshold When were (or will) scientists willing to transition into clinical studies? (what considerations impacted this decision)

Protocol Development Studies Research on cell type, dosage and/or administration of NeuroRM for clinical trials

Qualitative Outcomes Patient’s reports following a trial (increased sensation in limbs, movement, bowel control)

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Quantitative Outcomes MRI, X-Ray, histology, scales used to measure outcomes.

Selecting Conditions to Target Criteria for selecting conditions to treat (need vs. commercial viability)

Selection Criteria Selection criteria (age, sex, progression of disease)

Regulation

Embryonic Review Procedures Review of Embryonic protocols, differences with other submissions completed by the interviewee

Enforcing Guidelines Ensuring guidelines are followed

Ethical Considerations Emerging ethical challenges

Ethics Review Structures How are protocols reviewed within institutions /nationally?

Funding Application Procedures for obtaining funds, institutions contacted

Good Practices Oversight How are preclinical and clinical practices set and observed during translation

Government Funding Government funders

Government Review National review measures, agencies, procedures

Institutional Protocol Review Institutional approvals (ethics committees etc.) International Collaboration - Regulations Regulations governing international partnerships

Invoked Regulations Regulations cited by stakeholders as important guides in translation (ISSCR, Helsinki, ICMR)

Issues Raised in Institutional Review Concerns raised during ethics review proceedings

National Collaboration - Guidelines Regulations governing national partnerships

Patents Cases of patents issues, process and details of each

Perceived Risks Identified risks of participant’s research

Perspectives on Regulations Reflections on the structure and enforcement of current regulations

Regulations Governing Collaborations

Other regulations governing partnerships including MOU’s, institutional mandates etc.)

Review Timeline Timeline from submission to review of a new protocol

Unregulated Practices Participant reflections on unchecked practices, cases of unregulated translation are included

Collaboration

Barriers to Collaboration Challenges in initiating and/or following up on collaborations Collaboration - Material Exchange Exchange of materials

Collaboration Initiation How partnerships were initiated

Communication Between Stakeholders

How is communication maintained in partnerships ( meetings, online, through student exchange)

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Finding Collaborators Where are partnerships forming (Between which groups and/or where in the country)

International Collaboration - Cultural facets Instances where differing cultural views on NeuroRM impact collaboration

International Collaboration - Initiation How international partnerships were initiated

International Collaboration - Partners Where are partnerships forming (nations, institutions, types of research)

International Collaboration - Regulations Regulations governing international partnerships

International Collaboration- Basic Research Examples of collaboration on preclinical research

National Collaboration - Basic Research Examples of collaboration on preclinical research

National Collaboration - Clinical studies Examples of collaboration on clinical studies

National Collaboration - Commercialization Instances where stakeholders collaborated to commercialize a product

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Appendix D: NeuroRM : Consent Form

STUDY INFORMATION AND CONSENT FORM

Research Project Title Neuroregenerative medicine in India: Regulation, Translation, and Collaboration (Part of the Neuro-Regenerative Medicine Ethics Global Perspectives Project) Investigators Mark J. Messih Claudia I. Emerson Peter A. Singer Abdallah S. Daar Funding Agency Canadian Institutes of Health Research Background and Purpose of Research This is a research project. The McLaughlin-Rotman Centre for Global Health (MRCGH), University Health Network (UHN) at the University of Toronto is currently examining factors contributing to innovation in Neuroregenerative Medicine, and we are interested in learning about the views of scientists and ethicists working in this field. The study seeks to understand the regulatory mechanisms in this field, how translation is fostered, role of collaborations and the ethical issues and challenges encountered by researchers and the strategies used to address them. Invitation to Participate You have been invited to participate in a one-on-one, face-to-face interview. You will be asked about your views and experiences with respect to research, clinical practices, regulation and application of neuro-regenerative medicine.

Participation Participation in research is completely voluntary. Even if you agree to participate in this study, you may withdraw your participation at any time. You may refuse to answer any specific questions without any adverse consequences, and you may also speak freely ‘off the record’ when you wish. You choose to withdraw from the study after we have collected data from you, all data relating to you will be removed from the study.

Interview Procedure The interview will last approximately 40 minutes to one hour. The interview will be conducted by the investigators (Messih and/or Emerson) and it will be digitally recorded and transcribed. The investigators will ask for your consent at the start of the interview.

When and where will the study take place? This is a 3 year study commencing in January 2007 and taking place in several countries, including: Canada, China, Germany, India and USA.

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Risks and benefits of the study The foreseeable risk of participating in this study is minimal. In discussing neuroregenerative research that may involve the use of embryonic stem cells, you could potentially express views that are considered sensitive by members of some societies. Accordingly, you may not wish to be identified as the source of those views. Thus great care will be taken to ensure your anonymity, privacy and confidentiality, and that of your institution in handling all data, and in the release of study results. No identifiable data will be reported at any time. You can choose to speak freely ‘off the record’ at any time. The benefit to you the participant is in your role in helping to identify the factors that facilitate innovation in neuroregenerative medicine. As well, by sharing with others the challenges you face and how you deal with them, you are helping to inform ‘best practices’ for ethically responsible research that all can benefit from. Privacy and Confidentiality The one-on-one interviews will be digitally recorded and transcribed. All digital files and transcripts will be kept on a password-protected computer with access restricted to the research team. All field notes will be stored in a locked cabinet at the McLaughlin- Rotman Centre for Global Health, University Health Network at the University of Toronto. All raw data (audio-digital files and transcripts) will be stored in a locked cabinet, and only members of the research team at the MRCGH-UHN at the University of Toronto will have access. To protect participant privacy, no personally identifiable information will be released in study reports. Care will be taken to not identify any individual or institution directly, or through the presentation of unique variables that when combined could potentially identify the individual or institution. All members of the research team are subject to duties of confidentiality and professional conduct. Confidentiality can only be guaranteed to the extent of the law. Publication of Research Findings: We will publish our results in the appropriate peer-reviewed academic journals, policy briefs, and possible teaching materials. We will present the data at national and international conferences. Care will be taken to protect your identity and that of your institution in all of our public reporting activities. Following the completion of our analysis, we may contact you to make sure we captured your views correctly (referred to as ‘member check’). Compensation/Remuneration You will not be compensated for your participation. Your Rights as a Participant You waive no legal rights by participating in this study. If you have any questions about your rights as a research participant you may telephone the Director of the Research Ethics Review Office at 416-946-3389. You are being given a copy of this information sheet.

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I, , agree to participate in a study that Name of person

is examining issues related to regulation, translation and collaboration pertaining to neuro-regenerative medicine.

By signing this form, I am indicating that I:

1. Read and understood the Letter of Invitation and the Study Information Form, including

the purpose of the project, description, procedure, research team, and funding, as described therein.

2. Understand that the procedure involves open-ended (face-to-face) interviews with the study investigators, and that interviews will be digitally recorded and transcribed.

3. Understand that the information provided during this consultation may be used in academic publications and public presentations.

4. Understand that the only risks to myself and my institution from participation in this study foreseen by the researchers is potentially being identified as the source of an opinion deemed sensitive by society, and the consequences to myself and/or my institution that could potentially follow if that occurred.

5. Understand that I can withdraw from the study at any time without explanation. 6. Have not waived any of the legal rights that I have as a participant in this research

study after signing this form. 7. Have been given a copy of this consent form and the study information form.

Participant’s Printed Name Participant’s Signature Date

Investigator Name Date