CLINICAL TRANSLATION OF NEURO-REGENERATIVE …...underlying causes of dysfunction and disease [3]....
Transcript of 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.
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Table of Contents
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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!
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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!
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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.
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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
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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.
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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
Fronto-temporal dementia
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
Friedreich’s ataxia
Progressive supranuclear palsy
Progressive supranuclear palsy
Friedreich’s ataxia
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
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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.
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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.
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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
determining which agencies are involved and their role in clinical translation.
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
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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
37
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:
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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
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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
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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
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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
determining which agencies are involved and their role in clinical translation.
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
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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
64
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 neuro- regenerative 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