Type 1 Diabetes Clinical Research Resource Map · Letter of recommendation The Type 1 Diabetes...

Type 1 Diabetes

Clinical Research Resource Map

Type 1 Diabetes Clinical Research Resource Map

Letter of recommendation

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Version control and updates. Clinical research and resources will of course change over time. It is anticipated that this document will be updated regularly, as an ongoing and dynamic resource. Please check www.t1dcrn.org.au to ensure that you have the latest version.

A consultation and revision process has been undertaken to ensure the accuracy and completeness of this document and its relevance to the type 1 diabetes research community. An editorial board was convened to provide feedback and critical review of the document, and to inform the progression of this project in terms of further facilitating access to resources necessary for the effective delivery of type 1 diabetes clinical research in Australia.

Scientific Editorial Board: Dr Paul Benitez-Aguirre Associate Professor Shane GreyDr Stuart Mannering Associate Professor Jonathan Shaw

Document Authors:Dr Alisa KnapmanDr Julia WarningDr Dorota Pawlak

Design Coordinator:Amanda Chan

The following individuals are also acknowledged for their valuable contribution to this document: Anne Cullinan, Lyndal Howison, Emily Milligan, Randall Rowe, Mike Wilson and Sydney Yovic. Please refer to Appendix 1 for a list of the many researchers who have supported the preparation of this document.


Letter of recommendation

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Letter of recommendationThe Type 1 Diabetes Clinical Research Resource Map 2015 was prepared as a part of the Global Diabetes Research innovation Partnership between the Macquarie Group Foundation and JDRF Australia.

The Macquarie Group Foundation is delighted to support the development of the first Type 1 Diabetes Clinical Research Resource Map. This resource will provide researchers, funders and policy makers with significant insight into the type 1 diabetes clinical research landscape in Australia. Understanding our existing research strengths, resources, clinical research infrastructure, and collaborative networks will help to direct the future of Australian type 1 diabetes research, inform new policy and identify areas of scientific need.

Lisa George Head, Macquarie Group Foundation

Type 1 Diabetes Clinical Research Resource Map2

Contents

ContentsExecutive summary 5

How to use this type 1 diabetes clinical research resource map 6

List of acronyms and abbreviations 7

1 Introduction 8

1.1 Background 9

1.2 Aim 9

1.3 Scope 10

1.4 Methodology 10

2 Australian clinical research – from bench to bedside 11

2.1 Research and development pipeline for therapies and treatments 12

2.1.1 Key stages of the research and development pipeline 13

2.2 Type 1 diabetes clinical research objectives 13

2.2.1 Prevent 13

2.2.2 Cure 14

2.2.3 Treat 14

2.3 Clinical research institutions 15

2.3.1 Research strengths and resources 17

2.4 Summary 24

3 Australian clinical research projects 25

3.1 Phases of Clinical Trials 26

3.2 Clinical Research – the past 10 years 27

Spotlight: Environmental Determinants of Islet Autoimmunity (ENDIA) 28

3.2.1 Early and late phase clinical trial funding 29

3.3 Clinical project focus areas 30

Research Focus – the artificial pancreas 31

3.4 Australian participation in international clinical trials 32

Spotlight: Adolescent Type 1 diabetes Intervention Trial (AdDIT) 34

3.5 Improving delivery and impact of clinical research 35

3.5.1 Patient recruitment and engagement 35

Spotlight: Patient recruitment 36

3.6 Translational research 37

Spotlight: Dr Stuart Mannering 38

3.7 Summary 38

4 Australian clinical research funding 39

4.1 Major funders and available grant schemes 40

4.2 Comparison of clinical and basic research funding 43

NHMRC and JDRF – A 10-year partnership 44

4.3 Funding limitations 45

Reported funding limitations 46

4.4 Summary 48

Type 1 Diabetes Clinical Research Resource Map 3

Contents

5 Clinical research resources: accelerators and enablers 495.1 Databases and datasets 50 5.1.1 Australian databases and datasets 51

Spotlight: Cancer risk in people with diabetes 53 5.1.2 International databases and datasets 545.2 Biobanks and biospecimen collections 55 5.2.1 Australian biobanks and biospecimen collections 56

Spotlight: The Australian Childhood Diabetes DNA Repository 58 5.2.2 International biobanks and biospecimen collections 595.3 Summary 606 Clinical research resources: accessibility 616.1 Clinical research data sharing 62 6.1.1 Australian database accessibility 62 Spotlight: Australasian Diabetes Data Network 63 Barriers to data sharing 646.2 Biobank and biospecimen sharing 65 6.2.1 Australian biobank and biospecimen accessibility 65 Barriers to biospecimen sharing 66 6.2.2 Living biobanks 67 Spotlight: TrialNet Living Biobank 676.3 Data and resource linkage 68

Spotlight: T1D Exchange 696.4 Summary 707 Clinical research networks and collaborations 717.1 Australian clinical research networks 72 Spotlight: The Australian Type 1 Diabetes Clinical Research Network 737.2 International clinical research networks 747.3 Informal collaborations 76 7.3.1 National collaboration 76 7.3.2 International collaboration 777.4 Professional societies and groups 78 Spotlight: The Australasian Paediatric Endocrine Group 78 7.4.1 International professional societies 80 Barriers to collaborating 817.5 Summary 828 Looking to the future 838.1 Overview 848.2 Analysis 85 Key recommendations 86 Appendices and References 88Appendix 1 Contributors 89Appendix 2 Search terms used for online research 90Appendix 3 Major multisite clinical projects in Australia from 2005-14 91

References 93


Contents

List of figures

Figure 2.1 The medical research and development pipeline 12

Figure 3.1 Australian type 1 diabetes clinical projects conducted from 2005-14 27

Figure 3.2 Cost, duration and funding of stages of research along the development pipeline 29

Figure 3.3 Australian type 1 diabetes clinical research project focus areas from 2005–14 30

Figure 3.4 Type 1 diabetes-related patents filed and granted in Australia from 2005–14 31

Figure 3.5 Internationally coordinated clinical projects with Australian recruitment sites from 2005–14

32

Figure 3.6 Clinical research focus areas of multinational projects with Australian sites from 2005-14

33

Figure 4.1 Comparative funding of type 1 diabetes clinical research grants 2005-14 by NHMRC and JDRF

40

Figure 4.2 Amount spent on basic and clinical research funded or administered by NHMRC and JDRF from 2005–14

43

Figure 4.3 Proportion of basic and clinical research funded or administered by NHMRC and JDRF

44

Figure 5.1 Accelerators and enablers of research 49

Figure 6.1 Accessibility of Australian databases and datasets 62

Figure 6.2 Accessibility of Australian biobanks and biospecimen collections 65

Figure 8.1 Recommendations 1–5 addressing key stages on the research and development pipeline

86

List of tables

Table 2.1 Major Australian research institutions conducting type 1 diabetes clinical research 15

Table 4.1 NHMRC funding schemes available to clinical researchers 41

Table 5.1 Australian databases and datasets 51

Table 5.2 International databases and datasets 54

Table 5.3 Australian biobanks and biospecimen collections 56

Table 5.4 International biobanks and biospecimen collections 59

Table 7.1 Australian clinical research networks 72

Table 7.2 International clinical research networks 74

Table 7.3 Australian professional societies 79

Table 7.4 International professional societies 80


Executive summary

Executive summaryType 1 diabetes is an autoimmune disease with a complex origin that is caused by destruction of the insulin-producing islet cells in the pancreas, and at present there is no cure. It results in lifelong dependence on injected insulin and has a strong association with serious long-term health complications. The disease imposes a considerable medical, financial and emotional burden on individuals and families in Australia, as well as incurring substantial costs to the Australian health system.

Australia has made a significant contribution to the global advancement of type 1 diabetes research, but there remains an urgent need to develop new strategies and therapies to treat, prevent and ultimately cure type 1 diabetes. Clinical research is research that involves people, their tissues and/or their health information. Transforming promising new ideas developed in the laboratory into real-life therapies for people living with type 1 diabetes requires the efficient translation of research through all stages of development from the laboratory to human clinical research, and eventually adoption into clinical practice.

The Type 1 Diabetes Clinical Research Resource Map (the resource map) provides an analysis of the current type 1 diabetes clinical research landscape in Australia. This document will enhance researcher access to available clinical research resources by increasing visibility and providing a directory of existing databases, biobanks and networks. Analysis of existing resources also serves to highlight key areas of need, and to identify opportunities to accelerate the progress of Australian type 1 diabetes clinical research and further increase its global impact. Strengthening Australian type 1 diabetes clinical research capabilities will expedite the translation of laboratory research into human clinical trials, improving patient access to new therapies and treatments for type 1 diabetes and its complications.

The resource map is both a directory of currently available Australian resources and a vital source of information highlighting areas of need and key opportunities for maximising our existing resources, bridging research bottlenecks and improving the translation of type 1 diabetes research from the laboratory into new treatments and therapies that benefit people living with type 1 diabetes.


Executive summary

How to use this type 1 diabetes clinical research resource map The Type 1 Diabetes Clinical Research Resource Map provides a snapshot analysis of resources available to researchers undertaking clinical research related to type 1 diabetes in Australia. These resources include data repositories, biobanks, patient cohorts, funders, research networks and other infrastructure available in Australia and internationally.

StructureThe resource map is structured so that the reader can focus on the material they are interested in, without needing to read from cover to cover. Refer to the detailed list of contents for assistance. Colour coding is used to help the reader access the information they are looking for.

This document is divided into eight sections.

1. Introduction Provides an overview of the background, aims and scope of the resource map, and outlines the methodology used to obtain the information provided in this document.

2. Overview of current clinical research in Australia

Outlines the research and development pipeline, looks at type 1 diabetes research objectives provides an overview of the main clinical research centres.

3. Clinical research projects – the last 10 years

Lists registered clinical projects over the last 10 years, provides an analysis of Australian research strengths, and highlights some common problems faced in delivering clinical research.

4. Clinical research funding Provides an overview of the main funders of clinical research in Australia, the types of grants available, and current issues faced by researchers in relation to the funding mechanisms in place.

5. Clinical research resources – accelerators and enablers

A directory of Australian databases, datasets, biobanks and biospecimen collections, and a list of similar international resources accessible by Australian researchers.

6. Clinical research resources – accessibility

Looks at the accessibility of existing Australian resources, barriers to establishing shared resources, and existing models of global resource sharing and linkage.

7. Clinical research networks and collaborations

Provides an overview of national and international collaborations, including formal clinical research networks and professional societies, and informal collaborations between researchers and institutions.

8. Looking to the future Presents a broad summary and analysis of the type 1 diabetes clinical research landscape in Australia, including research strengths, areas of need, and key opportunities for accelerating research progress. Provides recommendations for future strategies to increase clinical research delivery and maximise global impact of Australian research.


List of acronyms and abbreviations

List of acronyms and abbreviationsAAPP Australian Artificial Pancreas Project

ACDDR Australian Childhood Diabetes DNA Registry

ACEIs Angiotensin converting enzyme inhibitors

ACR Australian Cancer Registry

ADA American Diabetes Association

AdDIT Adolescent Type 1 Diabetes Intervention Trial

ADDN Australasian Diabetes Data Network

ADEA Australian Diabetes Educators Association

ADS Australian Diabetes Society

ANZCTR Australian and New Zealand Clinical Trials Registry

ANZSN Australian and New Zealand Society of Nephrology

APC Artificial Pancreas Consortium

APEG Australasian Paediatric Endocrine Group

APS Australian Paediatric Society

ARC Australian Research Council

ASCR Adult Stem Cell Research Network

ASI Australasian Society for Immunology

ASMR Australian Society for Medical Research

CCTN JDRF Canadian Clinical Trials Network

CERA Centre for Eye Research Australia

CHW The Children’s Hospital at Westmead

CITC Clinical Islet Transplant Consortium

CITR Clinical Islet Transplant Repository

CPC The Charles Perkins Centre

CRE Centre of Research Excellence

CSANZ Cardiac Society of Australia and New Zealand

DA Diabetes Australia

DARP Diabetes Australia Research Program

DirecNET Diabetes Research in Children Network

DoH Department of Health

DRCR.net Diabetic Retinopathy Clinical Research Network

DTS Diabetes Technology Society

DVDC Diabetes Vaccine Development Centre

EASD European Association for the Study of Diabetes

EGFR Epidermal growth-factor receptor

ENDIA Environmental Determinants of Islet Autoimmunity

ENDO The Endocrine Society

ENSA Endocrine Nurses Society of Australia

FAME 1-EYE Fenofibrate And Microvascular Events in Type 1 Diabetes

HMRI Hunter Medical Research Institute

HPI Harry Perkins Institute of Medical Research

ICTRP International Clinical Trials Registry Platform

IDF International Diabetes Federation

IDS Immunology of Diabetes Society

IHMC International Human Microbiome Consortium

INIT II Intranasal Insulin Trial II

ISPAD International Society for Paediatric and Adolescent Diabetes

ITN Immune Tolerance Network

ITP Australian Islet Transplantation Program

NADC National Association of Diabetes Centres

NDI National Death Index

NHMRC National Health and Medical Research Council

NIDDK National Institute of Diabetes and Digestive and Kidney Diseases

NIH National Institutes of Health

NMD National Mortality Database

OECD Organisation for Economic Cooperation and Development

PLGS Predictive Low Glucose Suspend Study

PMH Princess Margaret Hospital

PSANZ Perinatal Society of Australia and New Zealand

RCH Royal Children’s Hospital

RCT Randomised controlled trial

REMOVAL Removing with Metformin Vascular Adverse Lesions in type 1 diabetes

SVHM St Vincent’s Hospital Melbourne

SVI St Vincent’s Institute of Medical Research

T1D Type 1 diabetes

T1DCRN Type 1 Diabetes Clinical Research Network

T1DGC Type 1 Diabetes Genetics Consortium

TEDDY The Environmental Determinants of Diabetes in the Young

TKI Telethon Kids Institute

TRI Translational Research Institute

TRIGR Trial to Reduce Insulin-Dependent Diabetes Mellitus in the Genetically at Risk

TSANZ Transplantation Society of Australia and New Zealand

UQDI University of Queensland Diamantina Institute

WEHI The Walter and Eliza Hall Institute of Medical Research

WHO World Health Organization

WMI Westmead Millennium Institute

Section 1 Introduction


1. IntroductionThe Type 1 Diabetes Clinical Research Resource Map was developed to identify resources available to researchers undertaking clinical research related to type 1 diabetes in Australia and to enhance researcher access to available resources by providing a directory of existing databases, biobanks and networks.

Importantly, it highlights ways to accelerate the progression of type 1 diabetes research. The capacity to conduct clinical research can be a bottleneck in translating research into real-life therapies, largely due to its expense. It is therefore important to develop strategies to maximise the outcomes of the clinical research that is undertaken, through restructuring funding, sharing resources and developing targeted partnerships. This resource map sets out to assist the process of accelerating and enabling Australian clinical research in type 1 diabetes, increasing its global impact, and making new treatments a reality for people living with the disease.

Introduction Section 1


1.1 BackgroundType 1 diabetes is an autoimmune disease that affects over 120,000 Australian children and adults. It causes lifelong dependence on injected insulin and carries the constant threat of devastating complications. At present there is no cure.

Ultimately, improving lives and curing type 1 diabetes requires the translation of basic science and applied research into treatments and technologies that are effective in people. This requires stepping out of the laboratory and moving into clinical research which involves human subjects or their tissues. As research progresses along the development pipeline into clinical phases the cost increases exponentially, as do the requirements for additional specialised clinical research tools and resources. This can result in difficulties securing the necessary resources to conduct clinical research1,2.

Australia has a strong foundation in basic type 1 diabetes research, as well as globally recognised clinician researchers and world-class research infrastructure3. Australia ‘punches above its weight’ in terms of type 1 diabetes clinical research output, with the sixth highest proportion of type 1 diabetes publications focused on clinical research (39%), ahead of the United States and United Kingdom and well above the world average of 27%4. However, the number of new clinical trials in Australia for all diseases has been declining over the past ten years1. Maintaining Australia’s global position as a leader in type 1 diabetes clinical research and improving Australian type 1 diabetes patient access to cutting-edge therapies requires the development of strategies to support type 1 diabetes clinical research capacity and facilitate research translation from ‘bench to bedside’.

Clinical and translational research requires specialised infrastructure and resources including staff to recruit and monitor patients, project management staff, access to human biospecimens and patient data, and statistical expertise. Access to these resources enables and accelerates research progress along the development pipeline. Many of these clinical research resources already exist in major Australian research institutions, but are geographically fragmented and often accessible only within each institution or informally through collaboration. Australia’s strong, collaborative network of researchers provides a fertile environment for building clinical research capacity, through connecting existing resources and investing in infrastructure, accelerating the translation of laboratory research into human clinical trials.

1.2 AimThe aim of the resource map is to provide an in-depth analysis of the type 1 diabetes clinical research landscape in Australia. This analysis includes:• an overview of type 1 diabetes clinical research currently being undertaken in Australia• an assessment of the resources currently available for type 1 diabetes clinical research in Australia• identification of the gaps in resources and infrastructure, as well as the barriers to developing and

sharing resources for type 1 diabetes clinical research in Australia• identification of opportunities for making current resources more widely accessible to the research

community to support and increase the impact of Australian type 1 diabetes clinical research.

The identification of key areas of need, including availability of biospecimens, patient cohorts and data repositories within the type 1 diabetes clinical research landscape will enhance effective investment into these areas.

Section 1 Introduction


1.3 ScopeThe scope of the analysis was set to include research at the stage of pre-clinical and translational research through to clinical research and clinical trials conducted at academic, hospital and non-profit research institutions. This was achieved through qualitative analyses of major research organisations conducting type 1 diabetes research in Australia and globally, through interviews and online research. Adoption of clinical research into clinical practice was not analysed for the purposes of this document.

Clinical and translational research analysed included research relating specifically to the prevention, cure and treatment of type 1 diabetes and its complications, undertaken from 2005–14. There was some overlap with type 2 diabetes in research related to diabetic complications; this research was not included unless type 1 diabetes was specified as a research focus. The scope of resources analysed included clinical and patient databases, data repositories, stored biospecimens and biobanks, major funders and large Australian and global clinical trial networks. International resources accessible to Australian researchers were included.

At present, there is little visibility of commercial research into type 1 diabetes and available resources stemming from the Australian commercial sector. As such, this analysis was largely limited to government, academic and other non-profit organisations.

1.4 MethodologyA qualitative review of major Australian research institutions conducting type 1 diabetes clinical or translational research was undertaken for analysis of current Australian type 1 diabetes clinical research and existing resources and infrastructure. This was achieved through on-site and telephone interviews with researchers currently active in type 1 diabetes clinical research. Active type 1 diabetes clinical researchers were identified through being current recipients of funding from JDRF or the National Health and Medical Research Council (NHMRC), through research networks and collaborative groups and through online research profiles. Twenty-five researchers from 19 research institutions were interviewed for this project. Interviews were semi-structured and conducted in conjunction with on-site visits of research institutions or over the phone. A list of contributors is detailed in Appendix 1 (page 89).

A quantitative analysis of Australian type 1 diabetes clinical trials and resources was conducted using online research with defined search terms detailed in Appendix 2 (page 90), and information obtained through interviews with researchers. Funding data was obtained from publically available online NHMRC funding datasets, from information published on the Australian Research Council (ARC) website and the Diabetes Australia (DA) website, and from an audit of JDRF and the Type 1 Diabetes Clinical Research Network (T1DCRN) funded projects from 2005–14. Data relating to type 1 diabetes clinical trials conducted from 2005–14 was obtained from the Australian and New Zealand Clinical Trials Registry, from the National Institutes of Health (NIH) clinical trials registry and from the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).

Australian clinical research – from bench to bedside Section 2


2. Australian clinical research – from bench to bedsideType 1 diabetes is a chronic autoimmune disease that arises when the insulin-producing islet cells in the pancreas are destroyed, resulting in lifelong dependence on insulin injections and potentially serious complications. The underlying cause of the immune destruction of islets is not yet understood, but research suggests that both genetic and environmental factors play a role.

The majority of clinical research in Australia and internationally can be broadly divided into three main objectives, which are to:

• prevent type 1 diabetes by stopping the onset of autoimmune destruction of islets • cure type 1 diabetes by replacing or restoring the body’s ability to produce insulin• treat type 1 diabetes by developing improved tools for managing diabetes or

treatments for its complications.

Section 2 Australian clinical research – from bench to bedside


2.1 Research and development pipeline for therapies and treatmentsType 1 diabetes research focuses on developing new strategies for treating type 1 diabetes and its complications, investigating ways to prevent type 1 diabetes from developing, and ultimately developing a cure. Before new therapies can become available, discoveries and advances made in the laboratory must first be tested in humans to ensure the safety and efficacy of the potential treatment. Prior to the stage of regulatory approval, the process of developing new therapies and treatments for type 1 diabetes can be divided into three stages:

Basic research: Basic research is the earliest stage of research, and is predominantly laboratory-based. It is carried out for the advancement of knowledge, and does not always have a specific goal or end-point.

Translational research: Translational research is the process of applying promising ideas and discoveries made during the process of basic research to the treatment and prevention of human disease. This can include testing new therapies in animal models, and initial testing in human tissues. Translational research is the critical bridge between basic and clinical research, and many potential therapies do not progress past this stage due to funding, safety, or efficacy issues.

Clinical research: Clinical research is research that directly involves humans, material obtained from humans, such as blood or tissue samples, or human data and health information. This stage encompasses patient-oriented research, epidemiological studies, and health economics and services research. Patient-oriented clinical research can generally be divided into two broad categories: observational studies, where data is collected and analysed according to a specific protocol but no treatment or intervention occurs; and interventional studies or clinical trials, which test the safety and efficacy of a particular medicine, treatment or therapy (see Section 3).

Figure 1: The medical research and development pipeline

Basic research

Translational research

Clinical research

Approval & availability

Delivery to patients

Funding$$$

Accelerators and enablers+ ++ +++

$$$

$



2.1.1 Key stages of the research and development pipeline

Developing new treatments and therapies to improve quality of life for people living with type 1 diabetes requires the effective translation of research from preclinical stages to human clinical trials. Each stage of the research pipeline differs in project design, cost, time to complete and resources required. The cost of research increases exponentially as it moves along the pipeline, and the number of patients required and the time to complete a project also increase substantially.

The 2013 McKeon review3 identified two stages along the research and development pipeline that have been termed ‘valleys of death’ in Australia. It is notoriously difficult for research to progress through these stages due to difficulties in attracting the necessary funding and resources. These ‘bottlenecks’ prevent many promising ideas and therapies from being further developed into real-life applications that benefit patients.

Translational research: The first ‘valley of death’ identified is the preclinical/translational stage, where a therapy has been developed to a point where no further funding for animal models or laboratory studies is available, but it is too early to show sufficient market potential to attract investment from the commercial sector.

Early-phase clinical research: The second ‘valley of death’ identified is the early-phase (phase 1 and 2) or pilot clinical studies stage. Here, a therapy has been shown to have potential, but further funding is required to investigate safety and efficacy, and to collect data that will support proposals to commercial funders. These trials are often too costly to be funded by the non-profit/government sector, but are still too high-risk to attract commercial funding.

Australia has a strong foundation in both basic and clinical type 1 diabetes research, but with the overall decline of clinical research in Australia1, increased effort must be focused on ensuring that type 1 diabetes clinical research is well supported and sufficiently resourced, and that strategies are developed to bridge the bottlenecks that hinder research progress. A number of clinical research resources exist that have the potential to accelerate and enable the progression of research along the development pipeline, but at present many of these are fragmented and scattered across Australia in hospitals, universities and other research institutions. Identifying and connecting these resources and supporting the establishment of strong research infrastructure would facilitate clinical research and ensure that Australian discoveries and advances can be effectively translated into positive patient outcomes.

2.2 Type 1 diabetes clinical research objectives

2.2.1 Prevent

Type 1 diabetes is not currently preventable, and there is no definitive method for predicting who will develop the disease. Intense research efforts focused on epidemiological evidence are currently trying to pinpoint genetic and environmental determinants contributing to the onset of type 1 diabetes. Australian researchers made a significant contribution to a large international study published in 20095 and co-ordinated by the Type 1 Diabetes Genetics Consortium (T1DGC; see page 54), which identified over 40 genetic markers contributing to the risk of developing type 1 diabetes (see also Australian Childhood Diabetes DNA Registry; page 58). Information generated from this study has been used to inform subsequent clinical studies such as Environmental Determinants of Islet Autoimmunity (ENDIA; see page 28), which investigates the interaction of environmental and genetic factors in the development of islet auto antibodies.



Other studies in vaccine development and immune modulation seek to identify ways of preventing the destruction of pancreatic islets. The Australian Intranasal Insulin Trial II (INIT II; see Appendix 3, page 91) is investigating whether exposure to intranasal insulin can prevent type 1 diabetes in people who test positive for type 1 diabetes autoantibodies6. Similarly, the international, multisite Pathway to Prevention study coordinated by TrialNet7 (page 75) is trialling the use of oral insulin to prevent the development of type 1 diabetes in susceptible people. The identification of targets for immunological therapies to prevent the destruction of beta-cells is also a priority for Australian researchers; however much of this research is at a pre-clinical stage.

2.2.2 Cure

Research into curing type 1 diabetes is typically focused on replacing or restoring the body’s ability to produce insulin. Current strategies include preserving or regenerating beta-cells after the onset of autoimmunity, or converting other cells in the body into insulin producing cells. The Australian Islet Transplantation Program (ITP) is an initiative that provides a ‘cure’ for some people with type 1 diabetes for a period of time, by transplanting islets from a donor pancreas into the hepatic portal vein8. At present this procedure is not accessible to the majority of type 1 diabetes patients due to a scarcity of donor islets and the necessity of taking lifelong immunosuppressant drugs. An alternative ‘cure’ that has received much attention of late is the implantation of encapsulated stem-cell derived islets. JDRF is funding development of this therapy in partnership with Viacyte, and the encapsulation system is currently in early-stage clinical trials in the United States9.

2.2.3 Treat

The management of type 1 diabetes is a daily burden, and even with the most careful blood glucose control serious complications can develop over time. Clinical research is ongoing to develop new and better ways to manage blood glucose, and to treat complications or prevent them from occurring. Australian type 1 diabetes clinical research has a strong focus on the development of new technologies for the management of type 1 diabetes. Australia is a world leader in the development of the ‘artificial pancreas’, which will eventually remove the need for manual blood glucose monitoring and insulin dose adjustment. Researchers at the Princess Margaret Hospital in Perth and St Vincent’s Hospital in Melbourne are currently trialling closed-loop and semi-closed loop systems (see page 31).

Targets for the development of drugs to treat or prevent the onset of complications such as kidney, eye and cardiovascular damage are also currently being investigated in Australia. The Reducing with Metformin Vascular Adverse Lesions in type 1 diabetes (REMOVAL) study is an international, collaborative study investigating the use of the drug metformin to prevent or slow the development of cardiovascular complications in adults with type 1 diabetes11. An Australian sub-study of the REMOVAL trial is being funded by the T1DCRN, and seeks to identify the mechanism by which metformin improves cardiovascular function.

Australian clinical researchers are targeting these three important areas of type 1 diabetes research at research institutions across the country. Each research institution identified for the purposes of this analysis has specific research strengths and specialties – in the area of research, the stage of the research pipeline that is focused on, and the resources and tools that are available.



2.3 Clinical research institutions Major academic and independent non-profit research institutions conducting type 1 diabetes clinical and translational research were identified as described in the methodology. There were 19 major research institutions identified in five states of Australia that conduct clinical and/or translational studies in preventing, curing or treating type 1 diabetes. Institutions located in the ACT, NT and Tasmania were not included in this analysis as the research conducted at these institutions is predominantly basic research.

An overview of each institution’s type 1 diabetes clinical research focus is provided in Table 2.1. Further details of each institution’s individual research strengths and expertise, as well as the resources and tools available for conducting clinical research are provided on pages 17 to 24.

In addition to the 19 major institutions identified, associated collaborating or affiliate sites make a valuable contribution to type 1 diabetes clinical research. Collaborating institutions as reported by researchers are detailed in Section 7.

Table 2.1: Major Australian research institutions conducting type 1 diabetes clinical research

InstitutionResearch priority Key type 1 diabetes clinical research area

NSW

Charles Perkins Centre (CPC)

Prevent • The gut microbiome and prevention of type 1 diabetes • Exercise and blood glucose control • Therapies to prevent and treat complicationsTreat

The Children’s Hospital at Westmead (CHW)

Prevent • Genetic and environmental determinants for risk and onset of type 1 diabetes

• Strategies for improved glycaemic control • Prediction and treatment of complications

Treat

Garvan Institute of Medical Research

Prevent • Genome-wide association studies to identify genetic component of type 1 diabetes and its complications

• Identification of target pathways to treat and prevent complicationsCure

Hunter Medical Research Institute (HMRI)

Treat • Development of improved algorithms for closed-loop systems. • Impact of other dietary factors aside from carbohydrate on

blood glucose • Impact of exercise on blood glucose control

Kolling Institute of Medical Research

Treat • Identification of target pathways to treat/prevent kidney complications

• Trials of new therapies to treat/prevent kidney complications

NHMRC Clinical Trials Centre

Prevent • Development of diagnostic assay of beta-cell death • Developing therapies to prevent/treat complications

Treat

Westmead Millennium Institute for Medical Research (WMI)

Treat • Lead site in the Australian Islet Transplantation Program • Studies investigating ways to improve outcomes in islet

transplantationCure



InstitutionResearch priority Key type 1 diabetes clinical research area

QLD

Mater Research Prevent • The contribution of advanced glycosylated end-products (AGEs) in progression of type 1 diabetes and kidney complications

• Improving blood glucose management with carbohydrate and exercise

Treat

University of Queensland Diamantina Institute (UQDI)

Prevent • Identification of immune pathways that contribute to autoimmunity• Development of immune therapies to stop or slow autoimmune

destruction of islet cellsCure

SA

Robinson Research Institute

Prevent • Lead site for the ENDIA study investigating early childhood and risk factors for the development of type 1 diabetes

• Participates in the Australian Islet Transplantation ProgramCure

VIC

Baker IDI Heart and Diabetes Institute (Baker IDI)

Treat • Causes and treatments for complications including cardiovascular and kidney damage

• The role of glycation in complication development and the genomics of complications

Centre for Eye Research Australia (CERA)

Treat • Identification of drug targets to treat retinopathy and diabetic macular oedema

• Clinical trials of drugs to treat diabetic eye disease

Royal Children’s Hospital (RCH) Melbourne

Treat • The effect of blood glucose variability on neuronal function and cognition

• Psychosocial outcomes of treatment interventions, and the effect of cognitive behavioural therapy on blood glucose management

St Vincent’s Hospital Melbourne (SVHM)

Treat • Lead site for clinical trials of closed-loop systems in adults, both in-clinic and outpatient

• Investigate psychosocial impact of closed-loop systems as well as impact on blood glucose control

St Vincent’s Institute of Medical Research (SVI)

Prevent • Islet inflammation and immune destruction of islets • Investigation of the autoimmune process including the contributing

genetic factors, and identification of targets for treatments to prevent islet destruction.

• Participates in Australian Islet Transplantation Program.

Cure

Walter and Eliza Hall Institute of Medical Research (WEHI)

Prevent • Australian co-ordinating site for TrialNet • Vaccine development and immunotherapies for prevention

of type 1 diabetes

WA

Harry Perkins Institute of Medical Research (HPI)

Prevent • Lead Australian site for the Type 1 Diabetes Genetics Consortium. • Identification of genes that predispose individuals to developing

type 1 diabetes

Princess Margaret Hospital (PMH)

Treat • Largest paediatric T1D clinic in WA, provides large cohorts of patients and support staff for clinical trials

Telethon Kids Institute (TKI)

Treat • Lead site for the Predictive Low Glucose Suspend study with PMH. • Development of closed-loop systems including automatic

insulin-suspend feature on insulin pumps • Algorithm development for closed-loop systems, including the

effect of various lifestyle parameters on blood glucose levels



2.3.1 Research strengths and resources

Each major research institution identified for the purposes of this analysis has specific research strengths and specialties – in the area of research, the stage of the research pipeline that is focused on, and the resources and tools that are available. Many institutions participate in large, multisite clinical trials. For further details, please see Appendix 3 (page 91).

Research area key:

Prevent Cure Treat

Resources key:

Clinical trials staffStaff dedicated to conducting and managing clinical research, including project managers, research nurses, research coordinators, data and sample managers, biostatisticians and administration staff.

Clinic databaseDatabases containing clinical information of patients captured during clinic visits or as part of a research project.

Patient cohortsAccess to patient cohorts for recruitment into clinical research projects.

Stored biospecimensStored blood, urine, saliva and other tissues obtained from patients during clinic visits or as part of research projects.

New South Wales

Charles Perkins Centre

Prevent Treat

The Charles Perkins Centre (CPC) opened in 2014 and is an initiative of the University of Sydney. CPC specialises in metabolic disease research including type 1 and type 2 diabetes, as well as obesity, cardiovascular disease and related conditions. Type 1 diabetes clinical research focus areas include the investigation of short-chain fatty acids in prevention of type 1 diabetes, the impact of exercise on blood glucose control, as well as pharmacological therapies for the treatment and prevention of complications. Researchers at CPC have access to clinical databases, patient cohorts and biosamples through the closely affiliated Royal Prince Alfred Hospital (RPAH) in Camperdown. The Clinical Research Facility, once completed, will comprise of dedicated clinical trial staff such as project managers and research nurses, and will facilitate the CPC’s goal of translating research findings from the University of Sydney into real-world applications.

www.sydney.edu.au/perkins



The Children’s Hospital at Westmead

Prevent Treat

The Children’s Hospital at Westmead (CHW) was opened in 1880 as the Sydney Hospital for Sick Children, and in 1906 it expanded and moved to Camperdown, before relocating to Westmead in 1995. In 2010 it became part of the newly formed Sydney Children’s Hospital Network, and is currently the largest paediatric centre in NSW. The Institute of Endocrinology and Diabetes at CHW is affiliated with the University of Sydney and conducts clinical research investigating the prevention of type 1 diabetes and its complications. CHW has been a part of a number of large multisite trials coordinated in Australia and internationally. Researchers at CHW have access to dedicated clinical trials staff, and are contributing patient clinical data to the Australasian Diabetes Data Network (ADDN, see page 63). Biospecimens from children with type 1 diabetes are stored, including blood, urine, saliva and other tissues.

Multisite Clinical Projects: ACDDR, ADDN, AdDIT, ENDIA, INIT II, TrialNet, TRIGR, PLGSwww.chw.edu.au


Prevent Cure

The Garvan Institute of Medical Research, first established in 1962, conducts research into the immunological factors that lead to the destruction of insulin-producing beta-cells, and aims to discover ways to regenerate beta-cells in the body. Researchers at the Garvan are also investigating the entire genome sequence of people with type 1 diabetes in order to pinpoint genes that increase the chances of a person developing type 1 diabetes and/or the associated complications. In addition, researchers at the Garvan are part of a collaborative venture seeking to identify markers that will predict whether islet transplantation will be successful in individuals. The Garvan has a Clinical Research Facility with staff, beds and equipment dedicated to conducting a range of clinical trials, although there are currently no trials in type 1 diabetes being conducted.

www.garvan.org.au

Hunter Medical Research Institute

Treat

The Hunter Medical Research Institute (HMRI) was established in 1998 in partnership with the University of Newcastle and Hunter New England local health district. HMRI is dedicated to translating research discoveries made in the laboratory into clinical practice. Through HMRI’s connection to John Hunter Hospital and John Hunter Children’s Hospital, researchers have access to a large pool of patients of all ages and at all stages of type 1 diabetes. The HMRI clinical research focus in type 1 diabetes is on the development of an artificial pancreas, with particular emphasis on the development of algorithms to facilitate a fully closed-loop system. HMRI has permanent clinical trials staff comprising of research nurses and a study coordinator, and engages additional staff on a project by project basis. Researchers also have access to biostatistical expertise within the institution.

Multisite clinical projects: AAPP, AdDIT, ADDNwww.hmri.com.au




Treat

The Kolling Institute is located in the grounds of the Royal North Shore Hospital in Sydney. It was established in 1920, and its facilities were consolidated into a single new building in 2008. It is affiliated with the University of Sydney, and conducts medical research related to ‘lifespan’, including cancer, pain, and developmental and regenerative medicine. The Kolling Institute has a strong focus on research into kidney disease, particularly in relation to diabetic nephropathy. Most clinical research in this field investigates the repurposing of existing drugs for renal protection. Researchers have access to patients from RNSH with type 1 and type 2 diabetes, as well as tissue samples from kidney biopsies. The Kolling Institute does not have a dedicated clinical trials unit as most research is laboratory-based; however researchers do have access to the clinical trials unit at the Prince of Wales Hospital when required. At present the Kolling Institute is not participating in any multisite type 1 diabetes clinical trials.

www.kolling.usyd.edu.au

NHMRC Clinical Trials Centre

Prevent Treat

The NHMRC Clinical Trials Centre (CTC), established in 1988, is affiliated with the University of Sydney and specialises in designing and conducting clinical trials in collaboration with researchers worldwide. Type 1 diabetes clinical research at the CTC includes the development of assays to identify beta-cell death in new-onset patients and after islet transplantation, as well as clinical trials investigating therapies to improve type 1 diabetes management and/or prevent complications. The CTC has a range of staff dedicated to managing clinical trials, including project managers, research nurses, administration staff and a large biostatistics unit.

Multisite clinical projects: FAME 1 EYE, REMOVAL www.ctc.usyd.edu.au

Westmead Millennium Institute for Medical Research

Cure Treat

The new Westmead Millennium Institute (WMI) building was officially opened in October 2014. Closely affiliated with the University of Sydney and Westmead Hospital, WMI brings together 11 research groups focusing on major diseases including immune and infectious diseases, heart disease and cancer. Type 1 diabetes clinical research at WMI has a strong focus on transplantation, including islet, kidney and pancreas transplants. Its close proximity to Westmead Hospital and The Children’s Hospital at Westmead provides access to a substantial cohort of transplant patients. Research studies include examining the rate of complications after transplantation, immune modulation and induction of tolerance to avoid rejection of transplants, islet cell biology after transplantation, and the effect of transplantation on liver function. The Australian Islet Transplantation Program is coordinated at WMI in collaboration with St Vincent’s Institute of Medical Research (SVI), and the institute has access to clinical trials infrastructure and staff, both internally and through Westmead Hospital.

Multisite clinical projects: Australian ITPwww.wmi.org.au



Queensland

Translational Research Institute

Prevent Cure Treat

The Translational Research Institute (TRI) was opened in 2012 and is a unique, Australian-first initiative focusing on ‘bench to bedside’ medical research. TRI combines the expertise of four leading research institutions and an on-site biopharmaceutical manufacturing facility. In this way, TRI aims to accelerate research progress from laboratory discoveries to clinical applications. TRI partners, the University of Queensland’s Diamantina Institute and Mater Research perform type 1 diabetes clinical research.

www.tri.edu.au

Mater Research

Prevent Treat

Mater Research was opened in 1999 and is linked with the Mater Private Hospital, the Lady Cilento Children’s Hospital and the Mater Adolescent and Young Adult Centre (MAYAC). This large patient base is a valuable resource for recruitment into clinical trials, with the advantage of maintaining data continuity throughout adolescence and into adult care via the MAYAC transition clinic. Mater Research is involved in several large national collaborative clinical trials in type 1 diabetes, including ENDIA and ADDN, as well as investigating the presence of biomarkers in the blood to predict the development of kidney complications in people with type 1 diabetes. Mater Research has access to clinical research staff through the Mater networks, including research nurses and research coordinators.

Multisite clinical projects: AdDIT, ADDN, ENDIAwww.research.mater.org.au

The University of Queensland Diamantina Institute

Prevent Cure

Established in 2007, the University of Queensland Diamantina Institute (UQDI) conducts research in autoimmune diseases such as type 1 diabetes and rheumatoid arthritis. Type 1 diabetes clinical studies include identification of biomarkers to predict the development of type 1 diabetes in at-risk individuals, as well as testing immunotherapeutic drugs that may be repurposed to halt beta-cell destruction. Through linkages to the Princess Alexandra Hospital, the UQDI has access to a large pool of patients available for recruitment into clinical trials. The UQDI also has staff dedicated to conducting clinical trials including research nurses and administrators, and has access to the Clinical Trials and Biostatistics Unit located within the Princess Alexandra Hospital.

Multisite clinical projects: ADDNwww.di.uq.edu.au



South Australia

Robinson Research Institute

Prevent Cure

The University of Adelaide’s Robinson Research Institute (RRI) opened in 2009 and is a collective of internationally renowned researchers in human reproduction, pregnancy and child health. Type 1 diabetes clinical research at RRI is focused on identifying the genetic and environmental factors occurring in early life that influence the development of the disease. RRI in collaboration with the Women’s and Children’s Hospital (WCH) in Adelaide is the lead site for the ENDIA study (see page 28), and is also a participating site in the Australian Islet Transplantation Program (ITP) in collaboration with the Queen Elizabeth Hospital (QEH), where islets are prepared for transplantation into patients. RRI’s affiliation with WCH and QEH provides researchers with access to cohorts of pregnant women and newborns at risk of type 1 diabetes and adults with established type 1 diabetes, as well as access to dedicated clinical trials staff including project managers, research nurses and statisticians.

Multisite clinical projects: AdDIT, ENDIA, PLGSwww.adelaide.edu.au/robinson-research-institute

Victoria

Baker IDI Heart and Diabetes Institute

Treat

Baker IDI is an independent research institution established in 1926, and has a strong history of diabetes research. Type 1 diabetes research at the institute is mainly focused on the treatment and prevention of diabetic complications, with projects spanning basic laboratory research to larger-scale clinical studies. The Baker IDI Specialist Diabetes Clinic is one of the largest and most diverse diabetes services in Australia, providing a rich resource for patient recruitment for clinical studies. Baker IDI also has a Clinical Trials Unit, which comprises of clinicians, a research coordinator, research nurses and data managers dedicated to managing clinical trials.

www.bakeridi.edu.au

Centre for Eye Research Australia

Treat

The Centre for Eye Research Australia (CERA) is an independent research organisation established in 1996 and is located within the Royal Victorian Eye and Ear Hospital. CERA is also closely affiliated with the University of Melbourne. Research at CERA is focused on finding solutions to three major eye diseases – diabetic eye disease, macular degeneration and glaucoma. Current clinical projects related to type 1 diabetes include testing pharmaceutical therapies to slow down or prevent the development of diabetes eye complications, as well as the development of new screening methods for early detection of eye disease. CERA’s close proximity to St Vincent’s Hospital in Melbourne gives researchers access to type 1 and type 2 diabetes patients with eye complications who can be recruited for clinical trials. CERA has a well-established Clinical Trials Research Unit with a project manager, research nurse, epidemiologist, statistician and several research coordinators. To date, CERA has not participated in any type 1 diabetes specific multisite clinical trials.

www.cera.org.au



Royal Children’s Hospital

Treat

The new Royal Children’s Hospital (RCH) was opened in late 2011 in Melbourne, adjacent to the old RCH, which was built in 1963 and has since been demolished. RCH is the largest specialist paediatric centre in Victoria, and has the largest type 1 diabetes clinic in Australasia, providing care for approximately 1500 children and adolescents with the disease. RCH has a strong research culture and is affiliated with the University of Melbourne and the Murdoch Children’s Research Institute (MCRI). Clinical research in type 1 diabetes is focused on cognitive effects of abnormal blood glucose levels, including the effect of ketoacidosis at diagnosis on subsequent brain development, and the effect of fluctuating blood glucose on neural function. RCH also collaborates in several large-scale, multisite clinical projects such as PLGS and AdDIT. MCRI has recently established a clinical trials unit with staff dedicated to project and data management, statistical analysis, and randomisation.

Multisite clinical projects: AdDIT, ADDN, PLGSwww.rch.org.au

St Vincent’s Hospital

Treat

St Vincent’s Hospital in Melbourne (SVHM) is a major teaching, research and tertiary healthcare institution, affiliated with the University of Melbourne and St Vincent’s Institute of Medical Research (SVI). A number of specialist clinics are run at the hospital, including a multidisciplinary diabetes clinic, a young adults diabetes clinic, an insulin pump clinic and an islet transplantation clinic, providing a large and varied pool of potential patient recruits for clinical trials. Research at SVHM is mainly clinical, and investigates technology for managing diabetes. Projects include overnight closed-loop trials, comparison of efficacy of insulin pumps and continuous glucose monitors, and study of psychosocial factors associated with technology use. SVHM employs clinical trial support staff such as research nurses and data entry staff, and ethics and finance staff and biostatisticians are also accessible by researchers.

Multisite clinical projects: AAPP, FAME EYE 1www.svhm.org.au

St Vincent’s Institute of Medical Research

Prevent Cure

The St Vincent’s Institute of Medical Research (SVI) was first established in 1951 under the name of the St Vincent’s School of Medical Research. Renamed in the 1970s, SVI performs both clinical and pre-clinical studies into the causes and prevention of type 1 diabetes, and is also heavily involved with the JDRF-administered Australian Islet Transplantation Program. Clinical studies at SVI include testing of various immunosuppressive and beta-cell therapies after islet transplantation to preserve the life of the graft, and examination of the metabolic effects of islet grafts. Researchers at SVI are also testing the feasibility of repurposing certain pharmaceuticals to prevent beta-cell destruction in animal models, with the intention of taking these therapies to clinical trials in the future.

Multisite clinical projects: Australian ITPwww.svi.edu.au



Walter and Eliza Hall Institute of Medical Research

Prevent

The Walter and Eliza Hall Institute of Medical Research (WEHI) is Australia’s oldest research institution, established in 1915. WEHI has a focus on developing treatments and prevention for a range of diseases including type 1 diabetes, and is the Australian centre for the international research network TrialNet (see page 67). In addition to basic laboratory studies, WEHI has a Clinical Translation Centre, which is dedicated to moving laboratory-based discoveries into clinical trials, coordinated by the adjacent Royal Melbourne Hospital and other hospitals throughout Victoria and Australia. These affiliated hospitals provide a pool of patients and data available for clinical studies. Type 1 diabetes clinical studies at WEHI include development of intranasal insulin-based, immune therapies for prevention of islet destruction and investigation into the genetic basis for type 1 diabetes susceptibility.

Multisite clinical projects: INITII, TrialNetwww.wehi.edu.au

Western Australia

Harry Perkins Institute of Medical Research

Prevent

Established as the Western Australian Institute for Medical Research in 1998, the newly renamed Harry Perkins Institute (HPI) is a multisite centre that was established with a vision to enhance collaboration between Western Australian medical researchers. The focus of type 1 diabetes clinical research at HPI is to identify genes in type 1 diabetes patients and their relatives that are involved in the development of type 1 diabetes, and in its complications. Researchers at HPI established the Australian Childhood Diabetes DNA Repository in 2006, and have made major contributions to the Type 1 Diabetes Genetics Consortium (see page 59).

Multisite clinical projects: ACDDR, ADDN, T1DGCwww.perkins.org.au

Princess Margaret Hospital for Children

Treat

The Princess Margaret Hospital in Perth (PMH) was first established in 1909 as Perth Children’s Hospital, and was renamed in 1949. PMH is the only specialist paediatric hospital in WA and is a part of the Child and Adolescent Health Service run by the WA Department of Health. It currently runs a large, well-resourced type 1 diabetes clinic, and the vast majority of children diagnosed with type 1 diabetes in WA are funnelled through this clinic. PMH’s close affiliation with the Telethon Kids Institute (TKI) provides researchers at TKI with a large, accessible cohort of type 1 diabetes patients, which includes detailed longitudinal clinical data for each patient and biospecimens collected at diagnosis.

Multisite clinical projects: AAPP, ADDN, AdDIT, PLGSwww.pmh.health.wa.gov.au



Telethon Kids Institute, Perth

Treat

The Telethon Kids Institute (TKI) was established in 1990 and conducts research into the most common, costly and devastating chronic diseases of childhood, including type 1 diabetes. It is affiliated with Princess Margaret Hospital for Children (PMH) in Perth. Type 1 diabetes clinical research at TKI is focused on the development of new technologies such as closed-loop systems, or the artificial pancreas. TKI and PMH make up the lead site for the Australian predictive low glucose suspend (PLGS) study which is trialling an automatic shut-off feature on insulin pumps that is activated when a hypoglycaemic event is predicted by a sophisticated algorithm. The development of algorithms for calculating insulin dosage in closed-loop systems also includes investigating the effect of various lifestyle factors such as exercise on blood glucose. TKI has access to a large number of dedicated clinical trials staff, including project managers, research coordinators and biostatisticians, and patient cohorts through PMH.

Multisite clinical projects: AAPP, ADDN, AdDIT, PLGSwww.telethonkids.org.au

2.4 SummaryAustralian research institutions conduct research covering a broad range of focus areas in type 1 diabetes, with particular strengths in investigating ways to improve treatment of existing type 1 diabetes and its complications. Australia makes a strong contribution to large-scale, multisite, international clinical research, with over 75% of institutions surveyed participating in multisite clinical trials. The majority of major Australian research institutions have access to various clinical research resources including patient cohorts and patient data, stored human biospecimens, and dedicated clinical trial staff and infrastructure.

Australian clinical research projects Section 3


3. Australian clinical research projectsClinical research studies are defined as research studies involving human subjects, human tissue, or human data. Clinical research studies encompass observational studies and interventional studies.

Observational studies involve collecting data for a cohort of patients or a cross-section of the population, and comparing health outcomes according to a specific research protocol.

Interventional studies or clinical trials investigate the effect of a particular intervention such as a new therapy or treatment on health outcomes.

Observational studies are used to generate hypotheses as to the causes of disease or information on “real-world” situations and practices. The findings from observational studies may lead to the development of interventions which are then tested in clinical trials.


Section 3 Australian clinical research projects

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3.1 Phases of clinical trialsClinical trials are generally divided into phases according to the stage of development of the treatment or therapy12:

• Phase 1 clinical trials involve the first administration of an intervention to humans, usually to small numbers of healthy volunteers, and are primarily conducted to determine the safety, route of administration, and appropriate dosage of an intervention for later studies.

• Phase 2 clinical trials are normally the first trials in patients suffering from the condition for which the intervention is intended. The principal aim of these clinical trials is to determine the intervention’s efficacy and safety, and they are undertaken in a small number of closely supervised patients.

• Phase 3 clinical trials involve larger numbers of patients and are undertaken to determine whether the intervention confers a benefit in the disease for which efficacy was demonstrated in Phase 2 clinical trials, and to determine any adverse effects. Phase 3 clinical trials are undertaken if the Phase 2 clinical trials indicate the medicine has potential benefit that outweighs the hazards.

• Phase 4 clinical trials are those clinical trials undertaken after the medicine has been approved for the treatment of a particular disease. Phase 4 clinical trials are undertaken to compare new therapies to existing therapies, to see whether the new intervention has benefits. Phase 4 clinical trials are also undertaken to further investigate the intervention in the normal clinical setting of the disease, and include post-marketing surveillance.



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3.2 Clinical research – the past 10 yearsThe Australian and New Zealand Clinical Trials Registry (ANZCTR) is an online registry of observational and interventional clinical projects coordinated in Australia and New Zealand13. Registration of clinical projects in Australia is not mandatory, and thus data contained within the ANZCTR may not provide a complete picture of type 1 diabetes clinical studies conducted in Australia. The US National Institutes of Health online clinical trials registry clinicaltrials.gov, contains information on additional clinical projects coordinated and/or conducted in Australia11. In addition to projects registered on ANZCTR and clinicaltrials.gov, JDRF has a database of clinical studies it funded between 2005–14.

Australian coordinated type 1 diabetes-specific clinical projects registered on ANZCTR, clinicaltrials.gov and/or funded by JDRF are included in the data shown below.

Figure 3.1: Australian type 1 diabetes clinical projects conducted from 2005–14

2005Year

Num

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2006 2007 2008 2009 2010 2011 2012 2013 2014

5

10

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Total number of trials registered

Number of trials with commercial support

The number of registered clinical projects in Australia has been increasing since 2011. However, it is not clear whether this increase reflects a real increase in the number of clinical projects conducted or an increase in the frequency of project registrations. The average proportion of commercially funded clinical trials has also increased during this period.



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Environmental Determinants of Islet Autoimmunity (ENDIA)

Prevent

Coordinating institution: Robinson Research Institute – University of Adelaide

Principal investigator: Professor Jenny Couper

Lead site: Women’s and Children’s Hospital, SA

Affiliate sites: Children’s Hospital at Westmead, NSW; Mater Hospital, Qld; Prince of Wales Hospital, NSW; Princess Margaret Hospital, WA; Royal Hospital for Women, NSW; Royal Melbourne Hospital, Vic.; Royal Women’s Hospital, Vic.; Sydney Children’s Hospital, NSW; Walter and Eliza Hall Institute, Vic.

Funding: Helmsley Charitable Trust, JDRF, NHMRC

Project overview: The incidence of type 1 diabetes has rapidly increased over the past 20 years. Genetic susceptibility within the population has not changed significantly during this time, which suggests that environmental factors are involved. The ENDIA study aims to identify these environmental triggers so that they can be modified or avoided to prevent the development of type 1 diabetes.

A total of 1400 pregnant women whose baby will have an immediate family member with type 1 diabetes will be enrolled in the study, and the baby will be followed while still in utero through to early childhood. Genes and environmental influences such as weight gain, nutrition, viral infection and physical activity will be studied in mother and child before and after birth to find out what increases the risk of diabetes or protects the child from developing diabetes.

The hypothesis of this study is that environmental factors during pregnancy and early childhood affect the development of the microbial population in the gut, called the microbiome. The ENDIA study aims to determine the combination of environmental and genetic factors that alter the microbiome in such a way that an autoimmune attack of the islets is triggered, leading to type 1 diabetes14.

ENDIA study research team



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3.1.1 Early and late phase clinical trial funding

As an intervention progresses through the phases of the clinical trial process, the risk of failure due to safety and efficacy issues decreases, while the cost increases exponentially. In Australia, early (phase 1 and 2) clinical trials or pilot clinical trials can cost up to $10 million, while late (phase 3 and 4) clinical trials may require between $15–50 million and take over 5 years to complete. Australia is one of the most expensive countries for conducting clinical trials, increasing the difficulty in attracting funding from the commercial sector, which is increasingly outsourcing clinical trials to other, lower-cost countries1.

Figure 3.2: Cost, duration and funding of stages of research along the development pipeline

Basic research


Clinical research



Funding$$$ $$$

$

Funding Largely public: government,

university and other non-profit

Mix of government

and commercial funding

Largely commercial: pharmaceutical and

biotech industry

Late phase

Early phase

Average cost Variable $200K–$1M over 2–3 years

Up to $10M over 5 years

Up to $15M–$500M over 5+ years

It is difficult to secure the necessary funding for clinical trials without commercial investment, particularly for late-phase trials. For commercial investment to occur, an intervention must be considered to be marketable and commercially viable. Early-phase clinical trials may not attract commercial funding due to the relatively high risk of failure, yet the cost of these trials can easily exceed the funding available from non-commercial funders. Even when an early-phase clinical trial is successful, the extremely high cost of later stage clinical trials can still preclude commercial investment, particularly when an intervention is only marketable to a relatively small proportion of the population, such as in the case of type 1 diabetes.

From 2005–14, only 18% of registered clinical trials were classified as phase 3 or phase 4 trials, and of these, 75% were commercially funded. In contrast, only 10% of the remainder of registered clinical trials were commercially funded. Increasing the number of late-phase clinical trials in Australia would accelerate the progress of therapy development and provide Australians with type 1 diabetes increased access to new and better treatment options.



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3.3 Clinical project focus areasThe three research areas with the heaviest focus for type 1 diabetes clinical research projects in Australia from 2005–14 were:• new technologies and other strategies to improve glucose control • the development of type 1 diabetes complications and how to prevent them• the psychological impact of type 1 diabetes and how behaviour can be modified to improve clinical

outcomes.

The heaviest investment from the commercial sector was for projects in the area of glucose control and technology, with over a third of these projects receiving commercial support through direct funding or through provision of drugs or technology.

Figure 3.3: Australian type 1 diabetes clinical research project focus areas from 2005–14

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Acute and chronic complications arising from impaired glucose control in type 1 diabetes place a heavy burden on individuals and on the Australian health system. Almost 80% of costs associated with type 1 diabetes are direct health-related costs, with hospitalisations contributing the largest direct cost15. Clinical trials testing novel therapies for glucose control, new technologies and other ways to ‘treat’ type 1 diabetes are therefore of critical importance.

This is likely to account for the large proportion of trials in glucose control and complications, coupled with high commercial investment which increases funding availability. Research in this area is more likely to result in a product that can be patented with relatively high marketability. From 2005–14, 96% of type 1 diabetes-related patents filed and granted were in the area of ‘treat’ research, and this is reflected in the high level of commercial interest16.



31

Table 3.4: Type 1 diabetes related patents filed and granted in Australia from 2005–14

n Treat 48

n Cure 2

n Prevent 0

96%

4%

Research focus: The artificial pancreas

Treat

A major focus of clinical research into new technologies is the development of the ‘artificial pancreas’. Many research groups all over the world are working towards developing a closed-loop system that consists of a continuous glucose monitor connected to an insulin pump, which will automatically dispense the precise amount of insulin required. In 2006, JDRF established the Artificial Pancreas Consortium, a multimillion-dollar, multiyear initiative with a mission to accelerate the development of artificial pancreas technology. Consortium investigators seek to research and develop strategies which can be commercialised, to further the ultimate goal of developing a fully automatic, closed-loop system17. Australian consortium members are leading the way in this field, with the development of algorithms for accurately calculating insulin requirements, and trialling new devices in children and adults with type 1 diabetes.

The Predictive Low Glucose Suspend (PLGS) study, funded by the JDRF T1DCRN, is testing a new feature on insulin pumps that prevents blood glucose from dropping too low. Researchers on the PLGS study have developed a sophisticated algorithm which can predict an upcoming hypoglycaemic event based on previous blood glucose data. Insulin delivery is then automatically shut off, preventing hypoglycaemia from occurring18. This feature is an important step towards realising the goal of a safe, fully closed-loop system. In addition to projects that are conducted by members of the Artificial Pancreas Consortium, Australian researchers at St Vincent’s Hospital in Melbourne are trialling closed-loop and semi-closed loop systems in adults, both in the clinic and at home, and researchers across Australia are working towards the development of new, sophisticated algorithms for accurately calculating insulin dose.



32

3.4 Australian participation in international clinical trialsA number of large, multinational clinical trials have recruitment sites in Australia, with international coordinating sites. Registration of clinical trials is compulsory in the US, and the National Institute of Health’s registry clinicaltrials.gov lists both US and internationally coordinated trials, including those with recruitment sites in Australia. Additionally, the World Health Organization (WHO) supports the International Clinical Trial Registry Platform (ICTRP), which collates information listed on various clinical trial registries worldwide19.

The data presented below represent internationally coordinated type 1 diabetes specific clinical projects with recruitment sites in Australia that are registered on clinicaltrials.gov and/or the ICTRP.

Figure 3.5: Internationally coordinated clinical projects with Australian recruitment sites from 2005–14

2005Year

Num

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2006 2007 2008 2009 2010 2011 2012 2013 2014

1

2

3

4

0





33

The number of international trials that Australia participates in has remained stable over the past 10 years. A high proportion of international trials are funded by the commercial sector, with at least half of trials registered each year from 2005–14 receiving some commercial funding. This likely reflects the fact that it is difficult to run large, multisite, international trials without commercial funding due to their extremely high cost.

Similarly to clinical trials coordinated in Australia, the primary research focus of type 1 diabetes international clinical projects with Australian participation is the area of glucose control and technology, with 12 projects registered in the last 10 years. All of these received some commercial funding.

Figure 3.6: Clinical research focus areas of multinational projects with Australian sites from 2005-14

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34

Adolescent Type 1 diabetes Intervention Trial (AdDIT)

Treat

Coordinating institutions: UK – Cambridge University; Australia – Telethon Kids Institute; Canada – The Hospital for Sick Children

Principal investigator: Professor David Dunger

Lead site: University of Cambridge, United Kingdom

Australian affiliate sites: Children’s Hospital at Westmead, NSW; John Hunter Children’s Hospital, NSW; Mater Hospital, Qld; Monash Medical Centre, VIC; Princess Margaret Hospital, WA; Royal Children’s Hospital, Vic.; Sydney Children’s Hospital, NSW; Women’s and Children’s Hospital, SA

Funding: British Heart Foundation, Cambridge University Hospitals NHS Foundation Trust, Diabetes UK, JDRF, NHMRC, Novo Nordisk, Pfizer

Timeline: January 2009–June 2016

Project overview: People diagnosed with type 1 diabetes during childhood are at risk of long-term complications including cardiovascular and kidney disease, which can have a significant impact on quality of life and life expectancy. The risk of complications can be reduced by optimising blood glucose control, but this can be difficult to achieve, particularly during adolescence.

Antihypertensive drugs, angiotensin converting enzyme inhibitors (ACEIs) and blood lipid lowering drugs (statins) are often prescribed to adults with diabetes in order to prevent or slow the development of complications. The aim of AdDIT is to discover whether ACEIs and statins have a similar benefit in adolescents with type 1 diabetes.

AdDIT will investigate the safety of prescribing ACEIs and statins to adolescents, and identify any short-term benefits on blood pressure and blood lipids. When combined with insulin therapy, use of these drugs during adolescence could help to reduce the risk of developing long-term complications13.



35

3.5 Improving delivery and impact of clinical research Two key opportunities for improving the delivery and impact of type 1 diabetes clinical trials were highlighted by researchers during interviews. Increasing patient engagement and improving research translation from laboratory studies to human clinical trials were seen as areas for improvement in Australia. Other barriers related to funding and resources are addressed in later sections.

3.5.1 Patient recruitment and engagement

Effective and timely patient recruitment is an integral part of a successful clinical trial. Patient recruitment and retention is often unpredictable, and difficulty in recruiting sufficient patient numbers is the leading cause of missed deadlines and adds considerable costs to a trial.

Traditionally, the questions investigated in clinical research projects are primarily determined by investigators or industry. Several researchers interviewed mentioned that the perspective of the type 1 diabetes patient is not always included when setting research priorities, and this can result in a disconnect which may have flow-on effects such as reduced willingness to participate in clinical research. This is not limited to the field of type 1 diabetes, but is a common problem across the spectrum of clinical research undertaken in Australia. The McKeon review recommended that consumer engagement in setting research priorities and participation in a database should be a priority3. Currently, there is a lack of formal processes in Australia for surveying and engaging people living with type 1 diabetes and their families in shaping the direction of type 1 diabetes research.

There are many possible factors that could influence patient engagement and recruitment and at present, these challenges are not well understood. Institutions with high rates of successful patient engagement and recruitment may provide some insight into developing improved strategies that could be adopted on a wider basis. Increased patient engagement would enable researchers, funders and policy makers to make informed decisions around research priorities and policies that would have the highest impact on these individuals and their families. Addressing research areas important to people with type 1 diabetes could have the added benefit of increasing patient participation in clinical research projects.



36

Spotlight: Patient recruitment

Improving the efficiency of patient recruitment can have a significant impact on the time and costs associated with a clinical trial. A third of researchers interviewed spoke about problems with patient recruitment, and highlighted five key areas that are important for successful recruitment and retention:

• Making the personal connection: Effective patient recruitment and retention seems to be best achieved with a personal approach, for example through dedicated staff during clinic visits. Over half of the type 1 diabetes researchers interviewed who are actively involved in patient recruitment said they lack the resources to allocate sufficient staff to recruiting patients for trials.

• Identifying patient eligibility: Eligible patients are often identified through hospital and clinic databases; however the loss of data during the transition from paediatric to adult clinics means crucial historical information may be lost. Adult patients often see a private endocrinologist rather than attending a hospital clinic, and so they may not be visible to researchers as an eligible patient, or receive any information about participating in clinical trials.

• Going the distance: The logistics of distance can be a problem for Australia, in that patients from regional areas may find it difficult to attend a clinical trial centre. On the other hand, the centralised nature of diabetes clinics means a large proportion of patients are accessible through major centres. 20% of researchers suggested that coordinating research visits with routine clinic visits can help to alleviate this problem and assist in patient retention.

• Competing for patients: The relatively small population of Australia can lead to concurrent research projects competing for the same patient pool. Furthermore, the same patients may be contacted repeatedly to participate in trials. Nationwide co-ordination of type 1 diabetes trials would assist in minimising this problem.

• Recruiting healthy patients: Patient recruitment for prevention trials can be particularly problematic, as eligible patients are often healthy children. Parents may be reluctant to enrol their child to participate in an intervention with an unknown outcome, and may be unwilling to dedicate the necessary time and effort when there is not an obvious benefit.



37

3.6 Translational research “A chasm has opened up between biomedical researchers and the patients who need their discoveries.”

– Butler (2008). Translational research: Crossing the valley of death. Nature.

The development of new therapies and treatments for type 1 diabetes begins in the laboratory. Potential treatments are initially developed in vitro and investigated using animal models to demonstrate their effects and safety. Many promising treatments never progress to human clinical studies due to the difficulty in securing the necessary funding to bridge the ‘valley of death’ between basic research studies and the first human trials21.

In addition to funding difficulties, many laboratory-based researchers and institutions lack the knowledge and resources required to co-ordinate and manage a clinical trial. In these cases, strong collaborations and networks can provide the necessary expertise and resources to support and nurture emerging clinical research centres (Section 7). Ideally, institutions conducting both basic and clinical studies have an established process for translating basic research studies into the clinical setting.

Accessible human tissue is a vital resource for many researchers wishing to translate basic research into clinical studies. Human biospecimens can be used to investigate whether disease processes and potential therapies demonstrated in animal models are physiologically relevant in humans, and provide proof-of-concept information that supports the feasibility of a potential clinical trial (sections 5 and 6).

Around 84% of major Australian research institutions involved in type 1 diabetes research conduct both basic and clinical studies.

Half of these have a clear translational process for connecting laboratory research to human clinical trials.

Only 16% actually make the connection.

84% 42% 16%



38

Spotlight : Dr Stuart Mannering

Dr Stuart Mannering is the Head of the Human T-Cell Laboratory at St Vincent’s Institute of Medical Research, and the recent recipient of the JDRF/Macquarie Group Global Innovation Award.

I’ve always been interested in human immunology as so much is still unknown about the field – there’s a lot of potential to do something really useful and make a real difference. Ultimately what I do is about understanding how the immune system works in type 1 diabetes, with the final goal of being able to better target subsequent research into finding a cure or prevention.

My recent research breakthrough was in finding immune cells in the donated pancreas of a person with type 1 diabetes – the first time this has ever been done. We couldn’t have done it without the generosity and strength of the family who chose to donate their son’s pancreas when he passed away. Having access to human samples is critical for researchers, and the lack thereof can be a real research bottleneck.

The important point to remember is that while doing research in human-based models with human tissue samples may be more difficult, it is worth the effort. Successes in animal models don’t necessarily translate to the same effect in humans, so starting from basic human research helps to set the scene before you go further.

It’s very difficult to fund the research that I do through traditional funding bodies – indeed, I think it would be true to say that many researchers spend up to 40% of their time trying to secure more funds and grant-writing when that time could be spent actually conducting research! Having an organisation like JDRF dedicated to funding type 1 diabetes research makes our lives as researchers a lot easier.

3.7 SummaryOver the past 10 years, Australian clinical research has had a strong focus on ‘treat’ projects, relating to improving glucose control, using new technology for daily diabetes management, and investigating ways to prevent or delay the onset of complications. This may be due in part to a higher availability of funding coming from the commercial sector, highlighting the benefit of involving industry in clinical research, and the need to extend this involvement to other areas of research such as ‘cure’ projects. Some common barriers that can impede the progress of research along the development pipeline include difficulties in recruiting and retaining patient volunteers for trials, and bridging the gap between laboratory studies and human clinical trials. Strategies to improve patient recruitment and facilitate translational research would help to accelerate research progress and improve delivery of Australian clinical research.

Australian clinical research funding Section 4


4. Australian clinical research funding Human clinical research is a major investment and much more expensive than laboratory-based research due in part to the time required to screen, recruit, treat and follow-up patients. The major funders of type 1 diabetes clinical research are government funders, large philanthropic organisations and industry.


Section 4 Australian clinical research funding

40

4.1 Major funders and available grant schemesGovernment funding of type 1 diabetes research, both basic and clinical, is mainly administered through the National Health and Medical Research Council (NHMRC). Other funders include JDRF, Diabetes Australia, the Australian Research Council and some industry and philanthropic funding.

For Australian type 1 diabetes clinical research, the NHMRC, JDRF and the Department of Health (DoH) are the major funders. From 2005–14, the NHMRC invested a total of $59 million into type 1 diabetes-specific clinical research22. JDRF invested $30.8 million into type 1 diabetes clinical research conducted in Australia, and DoH invested $20 million into the clinical stream of the JDRF-administered Australian Islet Transplantation Program (ITP) and $5 million into the JDRF-administered T1DCRN23.

Figure 4.1: Comparative funding of type 1 diabetes clinical research grants 2005-14 by NHMRC and JDRF

2005Year

$ m

illio

ns

2006 2007 2008 2009 2010 2011 2012 2013 2014

4

8

12

16

20

0

JDRF

NHMRC

JDRF funding includes DoH-funded projects that are administered by JDRF.

It is important to note that the JDRF-administered ITP ran from 2006-2011, contributing to the increased amount awarded by JDRF during this period.

National Health and Medical Research CouncilThe NHMRC is the primary funder of diabetes research in Australia. More than 85% of the researchers interviewed currently receive NHMRC funding. A range of funding opportunities are available for researchers, including project grants and career support schemes. There are some schemes that are focused more on clinical research such as Centres of Research Excellence, which supports research aiming to improve health outcomes and promote or improve translation of research outcomes into policy and/or practice.



41

Table 4.1: NHMRC funding schemes available to type 1 diabetes clinical researchers

Scheme Overview

Research Grants

Program Grants Broad based, multi-disciplinary and collaborative, supporting all health-related research – biomedical, clinical, public health or health services up to 5 years.

Project Grants Investigator-initiated research projects of up to 5 years, all health-related research. Single investigators or teams of up to ten chief investigators are supported.

Translational Grants

Centres of Research Excellence

Supports teams of researchers to pursue collaborative research and develop capacity in clinical, population health and health services research.

Development Grants Supports individual researchers, research teams, or a medical research company in partnership with a researcher/s at the early proof-of-concept stage for the development of a commercial product, process, procedure or service that has the potential to improve health care, prevent disease or provide health cost savings.

Targeted and Urgent Calls for Research

One-time solicitations for grant applications for funding for priority research in defined areas of need and when urgent research needs emerge.

People Support

Postgraduate Scholarships Support outstanding health and medical graduates to attain a research-based postgraduate degree (Doctor of Philosophy (PhD) or a Master’s Degree).

Early Career Fellowships Advanced training in health and medical research in Australia or overseas at the postdoctoral level.

Career Development Fellowships

Supports early to mid-career researchers in establishing their career.

Research Fellowships Support the very best medical and health full-time researchers during the most productive years of their research life to further develop as leaders in their field.

Practitioner Fellowships Funding for active clinicians and public health/health services professionals to undertake research that is linked to their practice or policy.

Translating Research Into Practice (TRIP) Fellowships

Targeted towards health care professionals and personnel, health systems and health policy makers to translate evidence into health care/public health improvements.

Infrastructure support

Infrastructure Support Scheme

Provides funding annually for overhead infrastructure costs to NHMRC approved Administering Institutions that are independent medical research institutes.

Equipment Grants Funding for equipment designed to support high quality health and medical research, as supported by the NHMRC or other competitive grant support.

Collaborative Grants

Partnership Projects Supports researchers and policy makers to influence health and well-being through changes in the delivery, organisation, funding and access to health services.

Partnership Centres Centres with national reach, bringing teams of researchers and decision-makers together to create better health services and health by collaborative work on priority themes determined by the needs of the health and health care systems.

NHMRC - EU Collaborative Research Grants

Supports Australian researchers in multinational research collaborative projects with international researchers that have been selected for funding under the European Commission’s Horizon 2020 Health or FP7 calls.

NHMRC – California Institute for Regenerative Medicine (CIRM) Collaborative Research Grants

Supports project work of up to 3 years duration conducted by Partner Investigators in Australia for the creation, design and testing of broadly applicable novel tools and technologies and the optimization, improvement, standardization or scale-up of existing tools or technologies for addressing translational bottlenecks to stem cell therapies.



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JDRF JDRF is the largest non-government funder of type 1 diabetes clinical research in Australia. JDRF has directly invested over $30 million in type 1 diabetes clinical research over the last 10 years, and has administered clinical research programs worth an additional $25 million.

In 2010, JDRF Australia established the Type 1 Diabetes Clinical Research Network (T1DCRN) with an initial $5 million grant from the Australian Department of Health (DoH). The T1DCRN aims to increase type 1 diabetes clinical research activity in Australia, enhance collaboration, and facilitate patient participation in clinical trials. The T1DCRN has funded a range of clinical projects with the original DoH grant, which include three major, multisite projects, nine proof-of-concept studies and five career support awards targeted at clinician researchers. This has had an appreciable impact on the increase in the amount of funding allocated to type 1 diabetes clinical research in recent years.

The T1DCRN was awarded a further $35 million grant over 5 years in 2014 as a Special Research Initiative from the Australian Research Council, and will continue to drive and support type 1 diabetes clinical research in Australia25.

The Australian Government Department of Health The Department of Health (DoH), formerly the Department of Health and Ageing, has invested into various targeted programs in type 1 diabetes clinical research. From 2005–09, DoH awarded over $30 million to JDRF to establish and manage the Australian Islet Transplantation Program (ITP)26. Over $20 million of the funding was directed towards the ITP’s clinical program, which included harvesting, transport and transplantation of donor islets in people with type 1 diabetes, and investigating ways to refine the clinical procedure. Much of the remaining funding was invested into the ITP’s basic research program, which consisted of supporting research into transplant therapy, associated health outcomes and effectiveness of the procedure.

The Australian Research CouncilThe Australian Research Council (ARC) supports research across all disciplines with the exception of clinical medicine. Clinical research is not a priority for the ARC; however during 2005–14 it supported two discovery projects, one future fellowship and five linkage projects that were directly related to type 1 diabetes27. The ARC has also recently awarded JDRF a Special Research Initiative of $35 million over 5 years to continue driving and supporting type 1 diabetes clinical research through the T1DCRN.

Diabetes Australia Research Program Diabetes Australia supports research into the prevention and management of all types of diabetes through the Diabetes Australia Research Program (DARP). The program funds one-year general research awards for up to $60,000, and these can be for basic, clinical or translational research. These awards have a particular focus on supporting young and upcoming scientists. In 2014, DARP awarded 11 grants totalling $719,498 to researchers conducting type 1 diabetes research, five of which were for clinical projects totalling $269,732. In addition, two Diabetes Australia Millennium Awards are awarded annually, one each in type 1 and type 2 diabetes. These awards are for up to $150,000 over two years28.



43

Commercial and industry funding

Industry funding of clinical trials is an important component of type 1 diabetes clinical research and 40% of researchers reported receiving some funding from industry to conduct clinical trials. Commercial funding of type 1 diabetes clinical research was not analysed for the purposes of this document.

Other funding

Funding is available through philanthropic funders as well as funding bodies not directly related to type 1 diabetes such as the National Heart Foundation and Kidney Health Australia.

A detailed analysis of available funding in this category was not performed for the purposes of this document.

4.2 Comparison of clinical and basic research fundingThe NHMRC and JDRF fund basic and clinical studies in type 1 diabetes. Many researchers surveyed felt that clinical research projects were under-represented in successful project grants awarded by the NHMRC. From 2005–14, clinical and translational research accounted for a third of type 1 diabetes research funded by the NHMRC and nearly two-thirds of research funded or administered by JDRF during this period was clinical or translational research. Funding of type 1 diabetes clinical research is likely to increase further in the coming years with the $35 million injection of funds into the T1DCRN by the ARC through JDRF.

Figure 4.2: Amount funded or administered by NHMRC and JDRF for basic and clinical research from 2005–14.

2005Year

JDRF research includes DoH funded projects that are administered by JDRF.

$ m

illio

ns

2006 2007 2008 2009 2010 2011 2012 2013 2014

10

20

30

40

50

0

Basic research

Clinical research



44

Figure 4.3: Proportion of basic and clinical projects funded or administered by NHMRC and JDRF from 2005–14

Combined NHMRC and JDRF basic and clinical research funding

Basic 55.6%

Clinical 44.4%

NHMRC basic and clinical research funding

Basic 65.0%

Clinical 35.8%

JDRF basic and clinical research funding

Basic 34.9%

Clinical 65.1%

NHMRC and JDRF – A 10-year partnership

JDRF has a long and effective co-funding partnership with the NHMRC, and through this partnership has co-funded a number of Program Grants, Centres of Research Excellence (CREs), and PhD top-up scholarships to support emerging scientists.

The partnership was first established in 2000, with the announcement of $10 million of funding to be provided equally by both parties for the establishment of the Diabetes Vaccine Development Centre (DVDC)29. This co-funding arrangement has continued, and in 2007 the NHMRC and JDRF announced five new jointly funded Special Program Grants for type 1 diabetes, totalling $10 million24. In 2014, JDRF and the NHMRC partnered again to co-fund three Centres of Research Excellence in type 1 diabetes, totalling a further $7.5 million over 5 years. In addition, JDRF supports early-career researchers in type 1 diabetes through funding of a PhD top-up scholarship for NHMRC PhD scholarship recipients.

This partnership has resulted in the release of targeted grants for type 1 diabetes research, and leveraged funding to increase support for Australian researchers. Together, the NHMRC and JDRF have fostered the development of some of Australia’s finest researchers in their investigations to find new ways to improve the lives of people with diabetes and to bring us closer to curing and preventing this condition in future.



45

4.3 Funding limitations A major limitation of conducting clinical research in Australia is the ability to secure the funding required. At present, the Australian Government spends 0.075% of gross domestic product on health and medical research, which is less than two-thirds of the Organisation for Economic Cooperation and Development (OECD) average of 0.118%21. Adding to issues of overall funding scarcity, clinical research is vastly more expensive than laboratory studies due to the time required to screen, recruit, treat and follow-up patients, as well as other indirect costs3.

The process of translating a new discovery into a therapy that is accessible to patients is lengthy and expensive. The average time for this process is 13 years, and less than 0.1% of promising therapies make it onto the market30. As research progresses successfully through the development pipeline, it becomes exponentially more expensive, especially in later-stage human clinical trials. The average time required to conduct a randomised controlled clinical trial has been estimated at 4,012 hours per 20 patients31. Securing funding for these relatively high-cost studies can be difficult, particularly for ‘high-risk’ studies where outcomes are not predictable. In fact, the number of new clinical trials conducted in Australia has been declining by an average of 13% per year, largely due to the high cost of clinical research in Australia, which has been driving commercially-funded clinical trials to lower-cost countries such as China and India3.

While the early stages of research are supported by a mix of government, non-profit, philanthropic and commercial funders, the high cost of human clinical trials means that funding of this stage of research is largely from industry and commercial organisations. Australia boasts some of the world’s best clinical researchers and state-of-the art infrastructure, yet the scarcity of available funding places severe restrictions on their ability to conduct clinical research.

All researchers interviewed named funding as a limitation to conducting their clinical research. Funding limitations that were identified by researchers fell into two broad categories: an insufficient pool of funds available, and grant durations that are too short to complete clinical projects. Specific issues reported by researchers are outlined on pages 46 to 47.



46

Reported funding limitations

Funding availability Funding security

Insufficient funding from non-commercial sector to support clinical projects

68% of researchers said that the total pool of available funding was insufficient, meaning that only a small proportion of promising ideas could be explored.

Government and other non-commercial grants are not sufficient to cover the cost of clinical research, yet it can be difficult to attract commercial investment, particularly in high-risk, early-phase clinical trials.

Insufficient funding to bridge the gap between basic and clinical research

63% of researchers that predominantly conduct basic research stated that many promising treatments developed in the laboratory and in animal models do not progress to clinical studies due to the high cost of clinical research in Australia. This has led to treatments discovered in the laboratory by Australian researchers being developed fully overseas.

Lack of infrastructure investment

Clinical research requires larger investment in infrastructure and administrative costs. 59% of researchers stated that they had difficulty securing funding for the necessary infrastructure to effectively conduct their research.

Difficult to compete with high-revenue diseases

Type 1 diabetes only affects a small proportion of the population, and is not a top-priority for commercial funders when compared with high-revenue diseases such as type 2 diabetes or cancer.

32% of researchers highlighted the need for more targeted grants to support type 1 diabetes specific clinical research.

Lack of funding for new ideas and researchers

The current funding structure is geared towards lower-risk projects that progress in incremental steps, making it difficult to get new, potentially transformative ideas off the ground. Three key opinion leaders highlighted the need for more funding for truly innovative ideas with high benefit potential.

Early-career scientists or clinicians wanting to move into research find it difficult to attract funding due to a limited track-record. 32% of researchers said more early career-support is needed for promising clinical researchers.

Repeatedly applying for funding is time-consuming

64% of researchers expressed frustration at the low success rates for applications made to major funders, resulting in many hours spent applying for smaller grants. 23% of researchers reported this had a marked impact on the time they were able to dedicate to conducting research.

Infrastructure development requires stable funding

The establishment and ongoing maintenance of clinical research infrastructure such as biobanks and databases requires ongoing funding. 56% of researchers would like to establish a shared biobank or database, but half of these said they were unwilling to invest time and money into infrastructure that may need to be abandoned when funding runs out.

Grant duration insufficient to conduct clinical trials

The average duration of a grant is 3–4 years, while the average duration of a clinical trial is at least 5 years from recruitment through follow-up.

32% of researchers said that the time-restrictions for the current grant system impacts their ability to conduct clinical research.

68%of researchers said

that the total pool of available funding was insufficient

32%of researchers said more early career support is needed

63%of researchers said there was

insufficient funding for translational

research

64%of researchers

expressed frustration at grant application

process

59%of researchers had difficulty securing

infrastructure funding

56%of researchers would

like to establish a shared biobank or

database

32%of researchers

highlighted the need for more targeted

grants


current grant duration impacts ability to conduct clinical

research



47

Reported funding limitations

Funding availability Funding security

Insufficient funding from non-commercial sector to support clinical projects

68% of researchers said that the total pool of available funding was insufficient, meaning that only a small proportion of promising ideas could be explored.

Government and other non-commercial grants are not sufficient to cover the cost of clinical research, yet it can be difficult to attract commercial investment, particularly in high-risk, early-phase clinical trials.

Insufficient funding to bridge the gap between basic and clinical research

63% of researchers that predominantly conduct basic research stated that many promising treatments developed in the laboratory and in animal models do not progress to clinical studies due to the high cost of clinical research in Australia. This has led to treatments discovered in the laboratory by Australian researchers being developed fully overseas.

Lack of infrastructure investment

Clinical research requires larger investment in infrastructure and administrative costs. 59% of researchers stated that they had difficulty securing funding for the necessary infrastructure to effectively conduct their research.

Difficult to compete with high-revenue diseases

Type 1 diabetes only affects a small proportion of the population, and is not a top-priority for commercial funders when compared with high-revenue diseases such as type 2 diabetes or cancer.

32% of researchers highlighted the need for more targeted grants to support type 1 diabetes specific clinical research.

Lack of funding for new ideas and researchers

The current funding structure is geared towards lower-risk projects that progress in incremental steps, making it difficult to get new, potentially transformative ideas off the ground. Three key opinion leaders highlighted the need for more funding for truly innovative ideas with high benefit potential.

Early-career scientists or clinicians wanting to move into research find it difficult to attract funding due to a limited track-record. 32% of researchers said more early career-support is needed for promising clinical researchers.

Repeatedly applying for funding is time-consuming

64% of researchers expressed frustration at the low success rates for applications made to major funders, resulting in many hours spent applying for smaller grants. 23% of researchers reported this had a marked impact on the time they were able to dedicate to conducting research.

Infrastructure development requires stable funding

The establishment and ongoing maintenance of clinical research infrastructure such as biobanks and databases requires ongoing funding. 56% of researchers would like to establish a shared biobank or database, but half of these said they were unwilling to invest time and money into infrastructure that may need to be abandoned when funding runs out.

Grant duration insufficient to conduct clinical trials

The average duration of a grant is 3–4 years, while the average duration of a clinical trial is at least 5 years from recruitment through follow-up.

32% of researchers said that the time-restrictions for the current grant system impacts their ability to conduct clinical research.


that the total pool of available funding was insufficient

32%of researchers said more early career support is needed

63%of researchers said there was

insufficient funding for translational

research

64%of researchers

expressed frustration at grant application

process

59%of researchers had difficulty securing

infrastructure funding

56%of researchers would

like to establish a shared biobank or

database

32%of researchers

highlighted the need for more targeted

grants


current grant duration impacts ability to conduct clinical

research



48

4.4 SummaryThe scarcity of available funding is a major barrier for Australian researchers conducting type 1 diabetes clinical research. The process of developing new therapies and treatments from laboratory studies to clinical trials is lengthy and expensive, and any point along the research and development pipeline that is insufficiently resourced results in a ‘bottleneck’ that slows research progress and positive health outcomes for patients. Clinical research projects have specific funding requirements that include larger grant amounts, longer grant durations and increased investment into infrastructure and clinical research resources. Researchers surveyed highlighted the urgent need for increased investment into clinical research by government and other funders in order to accelerate research progress through research bottlenecks. The Type 1 Diabetes Clinical Research Network by JDRF is a crucial driver of type 1 diabetes clinical research in Australia, by directing much-needed funds specifically to clinical and translational research.

Clinical research resources – accelerators and enablers Section 5


5. Clinical research resources: accelerators and enablers Clinical research requires sophisticated infrastructure and a wide range of tools and resources to achieve high impact, quality research. These resources include patient clinical databases, human biospecimens, and data generated from previous clinical projects. Researcher access to these resources can accelerate and enable the progress of type 1 diabetes therapy development through the clinical research pipeline. For example, important differences between rodent and human physiology are well documented, and researchers require improved access to human biospecimens to ensure that results from experimental models translate to humans. Improved access to human biospecimens could enable the translation of type 1 diabetes research through the preclinical stage, and accelerate the progression of potential therapies to human clinical trials.

This section provides a directory of existing resources held by individual researchers and institutions in Australia, as well as international resources that are accessible by researchers in Australia.

Figure 5.1: Accelerators and enablers of research progression along the development pipeline

Basic research


Clinical research



$



Section 5 Clinical research resources – accelerators and enablers

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5.1 Databases and datasetsDatabases containing information relevant to type 1 diabetes are vital resources for researchers undertaking clinical research. Databases vary greatly in the scope of information covered, ranging from clinic- and project-specific clinical databases, to population-wide databases capturing epidemiological and/or genetic data.

Clinical databases: Clinical databases contain patient information collected during routine clinic visits and consultations. These are usually housed within a hospital or clinic data system, with data entered by the clinicians themselves. Clinician researchers typically use clinical databases to identify and contact eligible patients for clinical trials, and to record longitudinal clinical data and treatment outcomes.

Project-specific databases: These databases contain information captured as part of a defined research trial or project. They often contain detailed, specialised information on a specific cohort of patients. The Environmental Determinants of Diabetes in the Young (TEDDY) study generated an example of a project-specific database containing genetic and immunological information on over 7000 children followed from birth throughout childhood (Table 5.2).

Collaborative databases: Collaborative databases capture information from a number of centres on a single database. Unlike project-specific databases, they often do not seek to answer a specific research question, but rather contain general clinical information and patient history. They have the potential to enable analysis of information pertaining to large numbers of subjects from varying backgrounds/ locations, and are generally accessible to the research community.

Population-wide databases: These databases usually capture a very small amount of information across a large number of subjects, for example the National Mortality Database (NMD, Table 5.1) which contains information on causes of death for individuals. Researchers may use these databases to find broad associations or linkages between clinical and environmental factors.



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5.1.1 Australian databases and datasets

A number of databases and datasets containing information relevant to type 1 diabetes clinical research exist in Australia. The information captured in these databases ranges from general clinical information to detailed and specific information from large, population-based cohorts.

Table 5.1: Australian databases and datasets

Database name Purpose and relevance to T1D Accessibility for research

Clinic

Baker IDI Heart and Diabetes Institute patient database www.bakeridi.edu.au

• Longitudinal database capturing clinical information from ≈ 1500 T1D patients seen during clinic visits

Not shared

Children’s Hospital Westmead (CHW) patient database www.addn.org.au/

• Longitudinal database with 4000 records from CHW paediatric diabetes centre

• 1300 active records with 100 incident cases per year

Shared via the Australasian Diabetes Data Network (ADDN)

John Hunter Hospital patient database www.addn.org.au/

• Longitudinal database capturing clinical information from 350 children and 900 adults with T1D seen during clinic visits

Paediatric data shared via the Australasian Diabetes Data Network (ADDN) Adult data not shared at present

Mater Hospital patient database www.mater.org.au

• Longitudinal database capturing clinical information from children and adults with T1D seen during clinic visits.

• The Mater network also has a ‘transition clinic’ database to prevent loss of patient data when transferring from paediatric to adult services

Paediatric data shared via the Australasian Diabetes Data Network (ADDN)Adult data not shared at present

Royal Melbourne Hospital (RMH) patient databasewww.biogrid.org.au

• Longitudinal database capturing clinical information from 600–700 adults with T1D seen during clinic visits

Accessible through BioGrid

Royal North Shore Hospital (RNSH) patient databasewww.nslhd.health.nsw.gov.au/Hospitals/RNSH

• Longitudinal database capturing clinical information from patients with T1D seen during clinic visits

Not shared

Royal Prince Alfred Hospital (RPAH) patient databasewww.sswahs.nsw.gov.au/rpa

• Longitudinal database capturing clinical information from 500 adults with T1D seen during clinic visits

Shared with collaborators

St Vincent’s Hospital Melbourne (SVHM) patient database www.svhm.org.au

• Longitudinal database capturing clinical information from 400 children and adults with T1D seen during clinic visits

Accessible through BioGrid

St Vincent’s Hospital Sydney patient databasewww.stvincents.com.au

• Longitudinal complications screening database of over 1000 people with diabetes, ≈ 30% of whom have T1D


Westmead Hospital Patient Database www.wslhd.health.nsw.gov.au/Westmead-Hospital

• Patient database capturing clinical information from islet, kidney and other transplant patients




52


Collaborative

Australasian Diabetes Data Network (ADDN) www.addn.org.au/

• A platform connecting paediatric T1D data from specialist centres across Australia

• Longitudinal database currently contains clinical information from over 5,500 children with T1D seen during clinic visits.

Accessible upon application and approval

Australian Rheumatology Association Database www.arad.org.au

• Longitudinal database of arthritis patient responses to 6–12 month questionnaires regarding long-term outcomes of disease and response to medical treatments.

• Contains information on patient responses to immunological therapies that may be relevant to T1D


BioGrid Australia www.biogrid.org.au

• 59,000 diabetes patient records relating to various diseases and health outcomes across five data owners

• T1D data from RMH and SVHM shared via this platform


Endocrine Genomics Virtual Laboratory (endoVL)www.nectar.org.au/endocrine-genomics- endovl-virtual-laboratory

• Created to provide seamless and secure access to clinical and bioinformatics data sets in a unified manner

• Contains data relating to various endocrine disorders, including T1D


VicNode www.vicnode.org.au/collections

• Provides mechanisms for storage, sharing, publication and long-term retention of Victorian research data

• Not specific to any disorder or health parameter; may be used for T1D research


Population-based

National (insulin-treated) Diabetes Register (NDR)www.aihw.gov.au/ national-diabetes-register/

• Collects data from people who began using insulin after January 1999 to treat type 1, type 2 or gestational diabetes.


National Diabetes Services Scheme (NDSS) Databasewww.ndss.com.au

• The NDSS provides services and products for people with all forms of diabetes

• Captures data on the majority of people with diabetes, including diabetes type, age of diagnosis, medication and consumables use


Australian Cancer Databasewww.aihw.gov.au/ australian-cancer-database

• Dynamic information on national cancer statistics such as incidence, trends, projections, survival and prevalence

• May be used to analyse cancer incidence and prevalence in individuals with other diseases including T1D (see page 53)




53


National Mortality Database (NMD) www.aihw.gov.au/ national-death-index

• The database comprises information about causes of death and other characteristics of the person, such as sex, age at death, area of usual residence and Indigenous status

• Can be compared with other databases such as the NDSS database to investigate causes and age of death for people with T1D


Population Health Research Network (PHRN)www.phrn.org.au

• The PHRN has been established to build a nationwide data linkage infrastructure capable of securely and safely managing health information from around Australia

• Not specific to any disorder or health parameter, may be used for T1D research


Project-specific

Australian National Diabetes Information Audit and Benchmarking Project (ANDIAB) www.adea.com.au/partners/nadc-2/andiab-project/

• ANDIAB was a project funded in 2009 collecting data on patients attending Diabetes Services across Australia

• ANDIAB2 collected data related to diabetes education and self-care


The Australian Childhood Diabetes DNA Repository (ACDDR) www.acddr.org.au

• Database capturing genetic information from 3000 Australian families, including T1D patients and their parents


Shared

Australian Twin Registrywww.twins.org.au

• A registry of over 30,000 pairs of twins willing to participate in clinical research

• May be used to investigate genetic and environmental components of T1D


Spotlight – Cancer risk in people with diabetes

The study ‘Cancer risk in people with type 1 and type 2 diabetes’, published in Diabetes Care in 201432, examined the rates of cancer in people with diabetes in Australia. Researchers from Baker IDI Heart and Diabetes Institute and Monash University obtained data on diabetes patients registered on the National Diabetes Services Scheme (NDSS) database, and linked this data with rates of cancer and causes of death on the Australian Cancer Registry (ACR) and the National Death Index (NDI).

Linkage of these large, population-wide databases resulted in the discovery that people with type 1 diabetes have an increased risk of certain types of cancer, particularly pancreatic and liver cancer in females.

More detailed databases with patient history and complication status could shed light on why this increase in cancer risk occurs, and may reveal certain lifestyle or environmental factors that could be modified to reduce cancer risk.



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5.1.3 International databases and datasets

In addition to Australian type 1 diabetes databases, several large international type 1 diabetes databases are available for use to researchers and the general community. Several of these databases capture information on both Australian type 1 diabetes patients and patients from other countries. These databases allow researchers to access data on larger numbers of patients than would otherwise be possible and can help to provide a global picture of people with type 1 diabetes.

Table 5.2: International databases and datasets

Name Details Accessibility for research

Collaborative

T1DBase www.t1dbase.org

• Web-based resource focuses on T1D genetics and genomics

• A set of datasets and tools across multiple species is openly available to researchers

• Candidate gene and genome-wide association/linkage studies are displayed

Openly accessible

Type 1 Diabetes Genetics Consortium (T1DGC) www.t1dgc.org

• Genetic database and clinical samples from over 6000 families with at least two siblings with T1D


The Human Biological Data Interchange www.ndriresource.org/Donor-Programs/ Family-Genetics-HBDI/36/

• Database of ≈6,700 families with T1D, detailed genealogical and medical history for 90,000 individuals

• Biological samples from ≈500 families• The National Diabetes Research Interchange

will conduct searches of the database on request to approved researchers


Type 1 Diabetes Exchange Clinic Registry www.t1dexchange.org

• Clinical information from over 26,000 individuals with T1D who have made their medical records available

• Biological samples and ‘living biobank’ also available


Belgian Diabetes Registrywww.bdronline.be

• The Belgian Diabetes Registry is a collaboration of more than 200 diabetologists, paediatricians and researchers

• It collects data of diabetic patients under age 40 and their relatives in a systematic and strictly confidential way


Project-Specific

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Data Repositorywww.niddkrepository.org

• Clinical project-specific data and biospecimens submitted by researchers and collected, processed and stored by NIDDK

• T1D clinical projects include: – The Genetics of Kidneys in Diabetes Study (GoKiND) – Genetic Association Information Network (GAIN) – Epidemiology of Diabetes Interventions and

Complications (EDIC) – Diabetes Control and Complications Trial (DCCT) – The Environmental Determinants of Diabetes in

the Young (TEDDY)• Searchable database to find specific trial or type of

data/biospecimen • Data are free of charge but access to biospecimens

incur a charge




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Name Details Accessibility for research

Population-based

EUBIROD – A European diabetes database www.eubirod.eu

• EUBIROD is a European Diabetes Register that has been developed using existing national/regional frameworks and the systematic use of BIRO technology

• Participants are connected through a system that automatically generates local statistical reports and safely collects aggregate data to produce international reports of diabetes indicators

The register is currently accessible by healthcare professionals but there are plans to expand accessibility

Scottish Care Information – Diabetes Collaboration (SCI-DC) Database www.sci-diabetes.scot.nhs.uk

• SCI-Diabetes provides a fully integrated shared electronic patient record to support treatment of NHS Scotland patients with diabetes

• Includes specialty modules for paediatrics, podiatry, diabetes specialist nursing and dietetics

Accessible through application to individual Scottish health boards

Swedish National Diabetes Register (NDR) www.ndr.nu

• The NDR is one of the largest national diabetes registries in the world, and was established in 1996

• Captures longitudinal clinical information from all people with diabetes in Sweden


5.2 Biobanks and biospecimen collectionsHuman tissue and blood samples are valuable resources that can be utilised for a range of clinical research projects, such as for understanding the risk factors that underlie complex diseases like type 1 diabetes, and at the translational research stage, where ideas and therapies developed in the laboratory can be tested in human tissue before progressing to human clinical studies. Human biospecimens are often stored in the form of a ‘biobank’, which can be defined as “an organised collection of human biological material and associated information stored for one or more research purposes.”33 Sharing biospecimens through formal biobanks increases researcher access to tissue or blood, enabling access to data representing a larger number of people than would otherwise have been available. Biobanking also allows biospecimens to be used for multiple research projects, preventing wastage, and can be of particular value for rare or specialised samples.



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5.2.1 Australian biobanks and biospecimen collections

Many of the major research institutions in Australia undertaking type 1 diabetes research have a collection of human biospecimens stored on-site; however in most cases these are not ‘biobanked’ and are available only to researchers within the institution or are shared informally with collaborators. Existing biobanks that are not specific to type 1 diabetes may also have relevance to type 1 diabetes clinical research.

Table 5.3: Australian biobanks and biospecimen collections

Institute/biobank name Location Details and relevance for T1D clinical research Accessibility

T1D specific

Kolling Institute kidney biospecimens www.kolling.usyd.edu.au

NSW • Stored kidney tissue samples from type 1 and 2 diabetes patients from 2010 onwards

Collaborators

Hunter Medical Research Institute biospecimens www.hmri.com.au

NSW • Stored blood and RNA samples from T1D diabetes patients obtained through clinic visits

Not shared

Westmead Kidney biobank www.wmi.org.au

NSW • Stored samples from islet transplantation projects linked to detailed clinical information

• Samples include DNA, lymphocytes, kidney and other tissue samples

Collaborators

Mater Hospital biospecimens www.mater.org.au

Qld • Stored blood and tissue samples from T1D patients obtained through clinic visits

Collaborators

St Vincent’s Institute biospecimens www.svi.edu.au

Vic. • Stored islets and pancreatic tissue samples from islet transplantation program

• Primary and secondary T cell clones isolated from islets/pancreas, lymph nodes, serum, plasma and DNA from T1D patients

Collaborators

St Vincent’s Hospital biospecimens www.svhm.org.au

Vic. • Stored DNA, blood and urine samples from T1D patients obtained through clinic visits

Collaborators

Princess Margaret Hospital biospecimens www.pmh.health.wa.gov.au

WA • Stored DNA, serum, urine samples taken at diagnosis of T1D and through clinic visits. Linked to detailed clinical information

Collaborators

The Australian Childhood Diabetes DNA Repository (ACDDR) www.acddr.org.au

WA • Stored DNA samples from children with T1D and their families

• ACDDR samples were accessible to researchers upon application between 2006 and 2011. No longer accessible except via collaboration (see page 58)

Collaborators

Sir Charles Gairdner Hospital Biobankwww.scgh.health. wa.gov.au

WA • Storage of DNA samples from patients with T1D extracted by WA DNA Bank

Collaborators



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Institute/biobank name Location Details and relevance for T1D clinical research Accessibility

T1D relevant

Genetic Repositories Australia www.neura.edu.au/GRA

NSW • DNA and gene samples from disease-specific and population-based studies

Accessible upon approval

Ventyx Wesley Research Institute Tissue Bankwww.wesleyresearch.org.au/tissue

Qld • Largest state-of-the-art bio-repository of human tissue and blood in Qld, with capacity to store millions of specimens with detailed clinical information attached

• Samples can also be requested prospectively and are obtained from patients at Wesley Hospital with a range of conditions


St Vincent’s Institute Biobank www.svi.edu.au

Vic. • Campus-wide collaboration storing frozen blood samples from patients with a range of conditions including T1D

• Samples include whole blood, plasma, serum and peripheral blood mononuclear cells (PBMCs)

Collaborators

Centre for Eye Research Australia biospecimens www.cera.org.au

Vic. • Stored blood and ocular fluid samples from patients with diabetic eye disease obtained through St Vincent’s Hospital clinic visits

Not shared

Western Australian DNA Bank www.gohad.uwa.edu.au/enabling-resources/biobanking

WA • Processes and stores DNA, RNA, serum and plasma for researchers who have obtained samples from various medical research projects including several diabetes-related projects


Australian Biospecimen Network www.abrn.net

Not applicable

• An online tissue specimen locator for cancer-related biobanks in Australia.

• Not T1D related, however has excellent online resources for protocols and guidelines for establishing tissue banks in Australia




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Spotlight – The Australian Childhood Diabetes DNA Repository

The Australian Childhood Diabetes DNA Repository (ACCDR) was a project funded by a NHMRC enabling grant from 2006–11. The ACCDR collected DNA samples across Australia from the saliva of over 1800 family trios of a child with type 1 diabetes and their biological parents. The samples are stored at a central repository at the Harry Perkins Institute of Medical Research in Perth.

The aim of ACDDR was to facilitate the identification of genes affecting the risk of developing type 1 diabetes. DNA samples were made available to all qualified Australian researchers upon ethics approval of their project. The project involved a number of major type 1 diabetes centres across Australia, including the Princess Margaret Hospital in Perth, the Women’s and Children’s Hospital in Adelaide, the Royal Children’s Hospital in Melbourne, the Mater Hospital in Brisbane and the Children’s Hospital at Westmead in NSW.

A number of important discoveries have come out of the ACDDR project, including a major study published in Nature Genetics in 20095 which identified 40 genetic loci contributing to the risk of developing T1D. The project was a 10-year collaboration with the T1DGC (see page 59), and is the largest linkage study in T1D ever conducted. Over 20 000 DNA samples were analysed worldwide, including DNA from 300 families from the ACDDR.

As NHMRC funding was not renewed, this valuable resource is no longer accessible to researchers outside of the ACDDR due to a lack of necessary resources and staff required to maintain the biobank and monitor access.



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5.2.3 International biobanks and biospecimen collections

Several large repositories of biospecimens relevant to type 1 diabetes exist overseas that are accessible to Australian researchers. These samples are available on application by researchers after study approval, and are often linked to databases providing detailed clinical information about the patient that the sample was taken from.

Table 5.4: International biobanks and biospecimen collections

Name Institution Location Details and relevance to T1D Accessibility

T1D Specific

EDIC Central Biochemistry Laboratorywww.portal.bsc.gwu.edu/web/edic/home

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH George Washington University

USA • Stored samples obtained as part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which is the follow-up study for the Diabetes Control and Complications Trial (DCCT)

• As there is a finite quantity of specimens in both the EDIC Central Biochemistry Laboratory (CBL) and the NIDDK Repository, some samples may have been depleted, and sample requests will take this into account


NIDDK Central Repository www.niddkrepository.org/home/

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH

USA • The NIDDK established its Data, Biosample, and Genetic Repositories in 2003 to make data and biospecimens from previously funded NIDDK studies available to the broader scientific community

• Includes samples from TrialNET, DCCT and EDIC studies (see Table 5.2)


nPOD www.jdrfnpod.org

JDRF USA • The JDRF funded nPOD biobank recovers and stores tissue from donor groups relevant to T1D research, and shares these samples with approved scientific investigators


T1DExchange Biobank www.t1dexchange.org/pages/biobank/

Benaroya Institute

USA • The T1D Exchange Biobank centralises thousands of biological samples, together with clinical, demographic, and study-derived information

• The T1D Exchange Biobank also coordinates a ‘Living Biobank’ of people with T1D who have consented to donate samples on demand (see page 69)


The Environmental Determinants of Diabetes in the Young (TEDDY) Biobank www.teddy. epi.usf.edu/

University of South Florida

USA • One of the main goals of the TEDDY study is to establish a central repository of data and biological samples including tissues, genetic material, and biological specimens for subsequent hypothesis-based research

Accessible for ancillary studies on approval

Type 1 Diabetes Genetic Consortium (T1DGC) www.niddkrepository.org/studies/t1dgc/

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH

USA • The T1DGC was a project was an international, multisite program to identify genes and alleles that determine risk for T1D

• The T1DGC has assembled renewable genetic materials and made research data available to the research community (see also page 54)




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Name Institution Location Details and relevance to T1D Accessibility

T1D Relevant

Biobanking Resource Centrewww.biobanking.org

Canadian Tissue Repository Network (CTRNet)

Canada • A directory of 24 international biobanks that gave permission to be listed

• No T1D specific biobanks are listed; however tissue obtained for transplant research and genetic repositories are included

N/A

Centre for Clinical and Translational Services (CCTS) Biobank www.uth.edu/biobank

University of Texas

USA • Over 14,800 human samples and related clinical data owned by contributing investigators within the Texas Medical Center

• Samples relate to autoimmune disorders, cardiovascular disease and cancer have been distributed to researchers since 2002


Danish National Biobank www.biobankdenmark.dk/

Danish Health Department

Denmark • Will contain more than 15 million biospecimens linked to Danish health registers containing lifetime health information

• Samples can be selected from individuals with certain diseases or health conditions such as T1D


Mayo Clinic Biobank www.mayo.edu/research/centers-programs/mayo-clinic-biobank

Mayo Clinic USA • A collection of samples, including blood and blood derivatives, and health information donated by Mayo Clinic patients

• Not focused on any particular disease, researchers can request samples from individuals with certain diseases or health conditions

Collaborators

UK Biobank www.ukbiobank.ac.uk

Collaborative UK • UK Biobank stores samples from 500,000 people aged from 40–69 years taken from 2006–10 with a wide range of health conditions including diabetes, cancer, heart diseases, stroke, arthritis and others

• Samples include blood, urine and saliva attached to detailed longitudinal information about the patients


5.3 SummaryThe majority of Australian clinical research institutions surveyed store patient data and biospecimens that are relevant to type 1 diabetes research. Patient data is routinely collected during clinic visits, along with periodic collection of blood and other tissue samples. As such, there is a vast amount of patient data and a large number of biospecimen repositories held at research institutions across the country and overseas, which are potentially available to researchers for type 1 diabetes clinical research.

Clinical research resources – accessibility Section 6


6. Clinical research resources – accessibilityA wide range of clinical research resources exist in individual research institutions across Australia. At present, many of these research accelerators and enablers are not shared with the wider scientific community. Increasing visibility and accessibility of these valuable resources enables investment into clinical research to be maximised, increasing research outputs and impact.


Section 6 Clinical research resources – accessibility

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6.1 Clinical research data sharingAs stated by the US National Institutes of Health (NIH), sharing research data is required to effectively and reliably translate research results into improving health34. While positive outcomes of clinical research are generally published, large amounts of data remain unpublished for various reasons, including being considered to be out of scope for the intended publication, or if the outcome resulted in little benefit to the patient. The Australian Code for the Responsible Conduct of Research states that Australian researchers have a responsibility to make research data available “for use by other researchers unless this is prevented by ethical, privacy or confidentiality matters”35. In 2013, an article in Nature36 claimed that over half of US clinical trials go unpublished, a scenario that is arguably similar in Australia. When data is not published or shared, research is wasted. Data-sharing reduces further waste by avoiding duplication and stimulates ongoing research by allowing new ideas to be generated from existing resources. This “bedside to bench” or reverse translation approach has resulted in new discoveries arising from unusual or unexpected outcomes from clinical trials, for example the discovery of a gene mutation which renders tumours exceptionally sensitive to the anti-cancer drug gefitinib37.

The concept of data-sharing is not new. In 1996 the “Bermuda Principles” were developed as part of the Human Genome Project, and expressly stated that all large-scale DNA sequence data should be made available in an open-access repository within 24 hours rather than waiting until publication38. This rapid sharing of DNA sequences has been credited with the identification of over 30 disease genes39. In 2003, the NIH released their policy requiring grant recipients to share data generated from NIH-funded research40. As a direct result of this policy, the NIH-funded type 1 diabetes project “The Environmental Determinants of Diabetes in the Young” (TEDDY) has developed a data-sharing policy and plans to make final data accessible on completion of the project41. Data generated through the TEDDY project will provide the scientific community with unprecedented longitudinal data from over 7000 newborns at risk of developing type 1 diabetes over 10-15 years, facilitating ancillary studies further investigating environmental risk factors for the development of type 1 diabetes.

6.1.1 Australian database accessibility

The majority of clinical researchers have access to clinical databases within their institution, with 74% of researchers surveyed routinely using this information as part of their research. Clinical databases were generally not shared outside of institutions; however several researchers contributed de-identified clinical data to centralised databases such as Biogrid or ADDN. Most researchers were supportive of the principle of shared databases, with 34% currently using external databases and 64% interested in contributing to and/or having access to external datasets.

Figure 6.1: Accessibility of Australian type 1 diabetes relevant databases

n Accessible through application and approval

n Not accessible outside institution

n Informal access through collaboration

n Publically accessible

8%

13%

17%

63%



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Spotlight: Australasian Diabetes Data Network Treat

What it is: The Australasian Diabetes Data Network (ADDN) project will capture clinical data from thousands of people living with type 1 diabetes on a single purpose-built database.

How it works: ADDN is an initiative funded by the T1DCRN and is being developed in partnership with the Australasian Paediatric Endocrine Group (APEG). De-identified patient data from five specialist tertiary centres across the country will be connected on a single platform, allowing researchers to access data that is representative of the whole population of people living with type 1 diabetes in Australia.

How it is used: ADDN’s consortium of researchers contributes baseline and longitudinal clinical data from its patients in a standardised format. At present, data from five major research centres across Australia are being incorporated into ADDN, which will then be accessible to external researchers upon application and approval by the consortium.

Australia has one of the highest rates of type 1 diabetes, affecting over 120,000 people, with 1000 new onset cases per year. Over half of people living with diabetes are children or adolescents, with most of these young people receiving their clinical care in central, tertiary academic centres. The ADDN project takes advantage of this centralised form of clinical care within Australia, and five major centres will recruit the majority (>80%) of new onset and existing cases of type 1 diabetes over three years.

The range of possibilities this opens up for research and clinical care improvements is enormous. Researchers will be able to answer questions such as how type 1 diabetes progresses over time, when complications develop, and how different models of care impact on clinical outcomes.

ADDN participants: the Casitovski family



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Barriers to data sharingMost type 1 diabetes clinical researchers understand the potential value of sharing databases and agree that access to more data could enhance their research. However, most researchers do not share their patient data. A number of issues were reported by surveyed researchers as being barriers to making patient databases more accessible.

Ethics and privacyPatient privacy is a barrier to sharing clinical data. Data must be de-identified, and ethics approval sought before it can be utilised for research.

Each research project must submit a separate ethics application, even when using the same database, and each database accessed may have different ethics requirements. This can add years to studies requiring access to several databases.

Data integrityClinical data is typically entered into databases by time-poor clinicians and may not be of sufficient quality to be useful.

Phenotypic data is often inconsistent due to a lack of standardised clinical classifications.

Researchers are often uncertain about the integrity of the data in external databases and may be hesitant to utilise them.

LogisticsShared databases require clear policies around access and contribution of data, and ensuring adherence to these policies can be time-consuming and require additional resources.

Sophisticated security measures are necessary for online databases to prevent inappropriate access and use and databases may also require a large amount of storage space.

Resources and infrastructureAdditional staff are usually required to input and maintain high quality, consistent data and monitor access to shared databases.

Funding for the infrastructure required is difficult to obtain, and researchers state it is difficult to justify allocation of scarce project funding to establishing a shared database.

Data consistencyDatabase platforms vary between institutions, which can make relevant data extraction and comparison difficult.

Researchers question the value of investing time and money into establishing a shared database, when it may not be useful to external researchers.



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6.2 Biobank and biospecimen sharingThe NHMRC has recognised the importance and value of biobanks for research and the translation of research. In 2012, the NHMRC released a National Biobank Strategy42 aimed at developing a national framework and model for creating biobanks, with the vision of minimising cost, streamlining ethics and approval, and increasing operational efficiency. Despite this, there is still little funding available from the NHMRC and other major funders that is dedicated to developing infrastructure that is required to establish and maintain a shared biobank.

6.2.1 Australian biobank and biospecimen accessibility

Of the type 1 diabetes clinical research institutions surveyed, 56% had biospecimens from type 1 diabetes patients in storage. None of these institutions had established a formal biobank with samples accessible to external researchers; however over half of researchers with stored samples reported sharing their samples informally with collaborators. A total of 45% of researchers from institutions without stored biospecimens routinely obtained samples from collaborators for their research.

The accessibility data below incorporates stored biospecimens reported by surveyed institutions and those identified through online searches.

Figure 6.2: Accessibility of Australian biospecimen collections

n Shared informally through collaboration

n Accessible

n Not shared

13%

27%

60%



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Barriers to biospecimen sharingAccess to biospecimens from shared biobanks was a key area of interest for researchers performing preclinical and genetic studies, while researchers specialising in clinical research and trials did not see sharing of human tissue samples as a priority. Researchers reported a number of barriers to formalising accessibility of biospecimens.

Funding44% of researchers would establish a biobank if dedicated funding was available.

Biobanks require continuous investment. Researchers could not justify investing scarce funding dollars into the infrastructure required to house and manage a biobank when funding may not be renewed to maintain the facility.

Clinical information24% of researchers indicated that clinical information related to biospecimens was often inadequate and unreliable. They highlighted the need for standardised clinical classifications of disease and complication stages.

A number of researchers required very specific samples with particular phenotypic data, and so preferred to obtain these samples themselves from patients known to them.

Ethics 20% of researchers identified Australian ethics requirements as overly burdensome, making the sharing and reusing of biospecimens extremely time-consuming. Researchers stated they preferred to obtain new samples themselves to avoid problems with obtaining ethics approval.

Logistics and management40% of researchers said the logistics of developing standardised procedures for collecting, processing, storing, sharing and tracking biospecimens was a disincentive for establishing a formal biobank, and they preferred to share samples informally.

A number of researchers indicated they would be willing to collect samples for a centralised biobank to lift the burden of management.

Utility80% of researchers surveyed do not access biospecimens from other institutions for their research. As such, they were not convinced that samples stored in a shared biobank would be utilised to an extent that would justify the investment of time and resources required.

Conversely, several researchers highlighted the finite nature of biospecimens, and were concerned about sharing irreplaceable samples.



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6.2.3 Living biobanks

‘Living biobanks’ are an alternative resource to conventional biobanks, and are comprised of a registry of participants willing to donate samples as required. Living biobanks can overcome many of the barriers to conventional biobanking, by allowing researchers access to ‘on-demand’ samples and enabling the collection of any clinical data or history required.

Many researchers expressed an interest in the development of a type 1 diabetes ‘living biobank’ over a conventional biobank for this reason. Mater Research in Brisbane currently has a registry of patients willing to participate in clinical research by donating samples, however this patient information is only available within the Institute.

Spotlight: TrialNet Living Biobank

Goal: The TrialNet Living Biobank is a resource developed in conjunction with longitudinal monitoring of subjects in the Pathway to Prevention Study, an observational clinical project examining the factors contributing to the development of T1D in susceptible individuals. The TrialNet Living Biobank aims to encourage ancillary studies to complement clinical research projects undertaken, and maximise value of available resources.

How it works: Select individuals who have been screened for eligibility in the Pathway to Prevention study can consent to become a part of the Living Biobank. Researchers may submit sample requests, and project proposals for approval. Approved requests are matched to individuals on the Living Biobank registry. If possible, requested samples are taken at the same time as samples required for the Pathway to Prevention study. Samples are collected de-identified before they are provided to researchers.

Research projects: TrialNet listed 29 ancillary studies in 2011 which examine biomarkers, genes, and immune factors involved in the development of T1D using the Living Biobank. The “Ancillary T-cell Study: studies of islet autoantigen-reactive T cells in subjects at risk for type 1 diabetes”43, was conducted in Australia at the Walter and Eliza Hall Institute of Medical Research and The Royal Melbourne Hospital.



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6.3 Data and resource linkageA recurring theme when it comes to sharing data and resources it that there is often insufficient or unreliable information associated with the resource, and that the infrastructure required to facilitate adequate, useful resource sharing is not in place. Patient data captured in clinical databases is often incomplete and may not capture the type of data necessary to be useful for a particular clinical project. The utilisation of biobanked specimens can likewise be hindered by a lack of annotated clinical data, and the accuracy of the data is not always clear, particularly when describing health status information where there may be no standard definitions (e.g. stage of complications). In addition to clinical data obtained from patients, data generated through clinical research projects is a valuable resource that can help to explain certain research outcomes and generate new project ideas and prevent duplication of research; however much of this data is lost if unpublished.

The linkage of patient clinical information, their biospecimens, and the outcomes of clinical research they participated in would be an ideal scenario that would maximise the value and usability of these resources. The logistics of setting up such a system, which would involve standardisation of collection and storage procedures, clinic software, data repositories and streamlining of ethics approval, is a major barrier to the realisation of such a goal. Such systems have successfully been established overseas, and these could be used to develop a similar model in Australia.



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Spotlight: T1D Exchange

Treat

Goal: The T1D Exchange is an initiative funded by the Helmsley Charitable Trust in 2009 as part of a greater vision to optimise research progress and mitigate the inefficiencies of translational and clinical research. T1D Exchange aims to optimise clinical research efforts by creating an integrated and patient-centric model with experts, data/evidence, samples and patients comprising an end-to-end system to support the entire process of discovery to delivery.

Model: The integrated model of T1D Exchange has several key components: A Clinic Network of 70+ clinics across the US, a Clinic Registry with data from 26,000+ people with T1D, a biobank housing a vast collection of biospecimens, and a living biobank comprised of people with T1D willing to donate samples on demand for research projects. In addition, T1D Exchange actively encourages patient engagement through its ‘Glu Community’, and conducts regular surveys and forums to help drive and shape the direction of T1D research. This model allows linkage of patient data to their samples, and provides a framework for conducting patient-centric clinical research.

Outcomes: The Residual C-peptide study run by the University of Florida is the first large-scale longitudinal study looking at residual insulin production in T1D patients of different duration of T1D and different ages of diagnosis. Approximately 1000 people registered on the T1D Exchange Living Biobank are providing samples for this study. The study aims to find out why some people with T1D continue to produce insulin for years after diagnosis, while others do not. This could help to identify ways in which insulin-production could be prolonged in people with newly diagnosed T1D.



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6.4 SummaryMany of the resources required for type 1 diabetes clinical research already exist in Australia, yet they are often fragmented and are not easily accessible by researchers across the country. At present, most of these valuable resources are not shared outside of collaborations, and the main reason for this seems to be the daunting prospect of setting up the required protocols and procedures, as well as obtaining the funding required.

Researchers who use human tissue samples for their research, particularly those who are aiming to translate their laboratory findings into clinical studies, expressed a strong desire for access to more human samples with reliable patient data attached. There is a clear opportunity for the establishment of a shared, nationwide type 1 diabetes patient database with longitudinal clinical information linked to patient biospecimens. This would maximise available resources and help to expedite research progress from the laboratory to new treatments and therapies for type 1 diabetes.

Clinical research networks and collaborations Section 7


7. Clinical research networks and collaborationsThe Australian type 1 diabetes research community is a strong, cohesive network of collaborating individuals and institutions. Formal collaborations, through clinical research networks and professional societies, have the purpose of supporting and accelerating clinical research outcomes. Informal collaborations develop through sharing knowledge, expertise and resources for a specific project or more generally. Scientific collaborations maximise available resources by facilitating the sharing of existing data, resources and expertise.


Section 7 Clinical research networks and collaborations

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7.1 Australian clinical research networksA number of clinical research networks are currently in place across Australia for a range of research areas or diseases, and several specifically support type 1 diabetes research. These networks generally consist of a group of researchers or research institutions that cooperate to streamline the process of designing and conducting clinical trials. Many Australian research networks are not directly related to type 1 diabetes, yet provide relevant resources and expertise to the type 1 diabetes research community.

Table 7.1: Australian clinical research networks

Name Purpose and relevance to T1D Key outcomes

T1D Specific

Diabetes Vaccine Development Centrewww.dvdc.org.au

• Provided a platform to translate type 1 diabetes research into improved clinical outcomes for the development of a T1D vaccine

• Closed in 2014, DVDC previously supported two clinical trials focused on preventing T1D.

The Australian Type 1 Diabetes Clinical Research Networkwww.t1dcrn.org.au

• Established in 2010 to positively impact the lives of people living with T1D through the support and promotion of clinical research in Australia (see page 13).

• Was awarded $35 million over 5 years from the ARC.

• Funds three large multisite projects, as well as a range of smaller innovative grants and career development awards, with a range of new projects to be funded.

T1D Relevant

Australasian Kidney Trials Network www.aktn.org.au

• Designs, conducts and supports clinical trials in kidney disease, including diabetic kidney complications

• Currently supporting ten clinical trials

Australian Clinical Trials Alliance www.clinicaltrialsalliance.org.au

• The Australian Clinical Trials Alliance (ACTA) supports and represents networks of clinician researchers that conduct investigator-initiated or ‘public-good’ clinical trials within the Australian health system

• Membership of over 50 clinical trial networks

• ACTA’s first project will be a comprehensive profile of clinical trial networks in Australia

Australian Paediatric Research Networkwww.aprn.org.au

• A network of Australian paediatricians that builds research capacity by involving more clinicians in research activities and enhancing patient recruitment

• Not specific to T1D however may be relevant due to childhood nature of T1D

• Currently supporting five clinical projects

Australian Stem Cell Network www.stemcellnetwork.org.au

• To further understand and to facilitate exchange of information of the science, medical applications, ethical and legal issues, and commercial potential of stem cells in an Australian and global context

• Not T1D specific but may be of relevance in the context of developing stem cell treatments for T1D

• Runs numerous professional workshops, publishes newsletters, provides a directory of stem cell resources for professionals

Biomedical Research Victoria www.biomedvic.org.au

• To support collaborative research and provide opportunities through sharing of resources, platforms and member expertise. The majority of major institutions conducting T1D clinical research in Victoria belong to this network

• Supports the Victorian Clinical Researcher Network (VCRN), the Victoria Platform Technologies Network (VPTN), and the Undergraduate Research Opportunities Program (UROP)



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MS Clinical Trials Network www.mstrials. org.au

• Established to facilitate the clinical trials process for multiple sclerosis (MS) in Australia and New Zealand, and to increase patient awareness of trials

• May have relevance to T1D research due to autoimmune nature of MS

• Currently supporting 26 clinical projects

NHMRC Clinical Trials Centre www.ctc.usyd. edu.au

• To achieve best practice in health care and improve outcomes in Australia and internationally through the use of clinical trials research for a range of conditions including T1D

• Supporting clinical trials in T1D, cancer, cardiovascular research and other areas

Nucleus Network www.nucleusnetwork.com.au/

• Owned by Baker IDI Heart and Diabetes Institute. Facilitates early clinical trials, has two sites to run early phase clinical trials

• Not specific to T1D but a valuable resource for running early clinical trials

• Performs diagnostic tests, statistical analyses; compounds/blinds pharmaceuticals, has a patient recruitment website

Paediatric Trials Network Australiawww.ptna.com.au

• Focussed on coordinating multisite clinical trials developed by researchers or industry partners, and strengthening the evidence base for the treatment of childhood diseases such as T1D

• Connected with nine research institutions

• Provides a platform for clinical data and project management including patient recruitment

Spotlight: The Australian Type 1 Diabetes Clinical Research Network

The Australian Type 1 Diabetes Clinical Research Network (T1DCRN) was established in 2010 by JDRF with a $5 million grant from the Department of Health and Aging. The network brings together expert research teams from multiple research fields to answer the most urgent and important type 1 diabetes research questions.

To date, the T1DCRN has funded three large-scale clinical projects, nine proof-of-concept projects and five clinician research support awards. The network hosts regular meetings and workshops to drive the research agenda and shape its strategic direction.

With continued funding from the Australian Research Council through a $35 million Special Research Initiative Grant, the T1DCRN will continue to build on its achievements, by supporting and funding type 1 diabetes clinical research projects, facilitating collaboration and resource sharing between researchers, nurturing emerging researchers and research centres, and building research capacity through support of infrastructure.



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7.2 International clinical research networksIn addition to Australian clinical research networks, a number of networks exist overseas, some of which are multinational networks and include Australian type 1 diabetes research centres. International clinical research networks increase research capacity by leveraging international research expertise, patient cohorts and resources.

Table 7.2: International clinical research networks


T1D specific

Artificial Pancreas Consortium (APC) www.jdrfconsortium.jaeb.org/

• Coordinated by JDRF and the Jaeb Center for Health Research, the APC is a network of researchers, clinicians, mathematicians and device manufacturers dedicated to the development of an artificial pancreas

• 24 participating clinics worldwide, including the Princess Margaret Hospital in Western Australia

Clinical Islet Transplantation Consortium (CITC)www.citisletstudy. org/index.html

• The Clinical Islet Transplantation Consortium (CITC) is a network of clinical centres and a data coordinating centre established in 2004 to conduct studies of islet transplantation in patients with T1D

• 11 participating centres • Studies conducted by the CITC

focus on improving the safety and long-term success of methods for transplanting islets in people with type 1 diabetes

Competence Network Diabetes Mellitus GERMANY www.kompetenznetz-diabetes-mellitus.net/

• To generate new insights into the development, prevention and treatment of diabetes mellitus. A key focus is to improve the translation of research results into everyday medical practice

• Five research topics with 24 projects have been selected for funding within the competence network diabetes mellitus

• Research topics are pre-clinical, biomarkers, cohort/biobank, intervention/biobank and epidemiology, health care and economics

Diabetes Research in Children Network (DirecNET)www.direcnet. jaeb.org/

• The world’s first research network dedicated to children with T1D, DirecNET is dedicated mainly to investigating glucose monitoring technology, and is also moving into studies investigating the neurological impact of T1D

• Consists of five clinical centres and has 14 completed clinical projects and three in progress.

• DirecNET also has public datasets available

Diabetic Retinopathy Clinical Research Network (DRCR.net) www.drcrnet.jaeb.org

• A collaborative network dedicated to facilitating multisite clinical research of diabetic retinopathy, diabetic macular oedema and associated conditions

• 109 participating sites throughout the US and Canada supported 24 clinical projects

Hvidore Study Group on Childhood Diabetes (Hvidore) www.hvidoregroup.org

• Hvidore aims to perform high quality collaborative multisite research in children and adolescents aimed at improving their diabetes care.

• Hvidore has members from 25 countries and has participated in clinical trials related to clinical care, immunotherapies and biomarkers of T1D.



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JDRF Canadian Clinical Trials Network (CCTN)www.jdrf.ca/jdrf-cctn/about-cctn/

• The JDRF CCTN is an initiative aimed at accelerating solutions for the management, care, and cure of T1D

• The CCTN has 17 clinical partners and affiliate sites, and is supporting 11 clinical projects in T1D

T1D Exchange Clinic Networkwww.t1dexchange.org/pages/ clinic-network

• The T1D Exchange Clinic Registry supports research in T1D by helping researchers characterise individuals living with the disease, conduct exploratory or hypothesis-generating analyses, and identify participants for future clinical studies

• 70 associated centres across US, 100,000 patients potentially available for trials.

• T1D Exchange also has biospecimens linked to patient data (see page x)

Type 1 Diabetes Trialnet www.diabetestrialnet.org

• TrialNet is a network dedicated to the study, prevention, and early treatment of type 1 diabetes (see page 67)

• 18 clinical centres working in cooperation with screening sites throughout the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand

• Over 50 publications from data collected in the Pathways to Prevention study since 2004

T1D Relevant

Adult Stem Cell Research Network www.ascrnetwork.com

• To provide a system for collaboration and communication among adult stem cell laboratories and researchers

• Not T1D specific, but may have relevance in the context of developing stem-cell therapies for T1D

• 37 associated centres internationally with 15 active clinical trials

Immune Tolerance Network (ITN) www.immunetolerance.org

• An international clinical research consortium supporting the development of clinical immune tolerance therapies for T1D and other conditions

• 10 countries, 178 clinical sites. Three active T1D trials, four completed T1D trials

International Microbiome Consortium (IMHC)www.human-microbiome.org

• To understand the role of the human microbiome in health and disease

• Not T1D specific, but may have relevance for identifying environmental factors contributing to T1D risk

• 12 participating centres are listed, including the CSIRO and NHMRC in Australia. Data-sharing is encouraged.

• Generating a shared data resource that will enable investigators to characterize the relationship between the human microbiome and human health and disease



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7.3 Informal collaborationsWhile a large proportion of type 1 diabetes clinical researchers have formal collaborations through clinical research networks, informal collaborations between researchers from different institutions are an integral part of the research process and form the backbone of the scientific community. These partnerships enable the exchange of knowledge, expertise and resources between researchers, facilitating new ideas and innovation, and allowing multidisciplinary clinical research projects to be undertaken with experts in each field.

7.3.1 National collaboration

The Australian type 1 diabetes research community has a diverse range of universities, hospitals, non-profit research institutions and industry within the informal collaborative network. Australian institutions reported by researchers as participating in collaborative type 1 diabetes clinical research are outlined below.

Universities

Australian National University

Deakin University

Flinders University

James Cook University

Monash University

Swinburne University of Technology

University of Adelaide

University of Melbourne

University of New South Wales

University of Newcastle

University of Sydney

University of Technology

University of Western Australia

University of Western Sydney

Hospitals

Austin Hospital

Blacktown Hospital

Children’s Hospital at Westmead

Concord Hospital

Fiona Stanley Hospital

Fremantle Hospital

Gold Coast Hospital

John Hunter Children’s Hospital

Mater Hospital

Mt Druitt Hospital

Nepean Hospital

Princess Alexandra Hospital

Princess Margaret Hospital

Royal Adelaide Hospital

Royal Children’s Hospital

Royal Melbourne Hospital

Royal North Shore Hospital

Royal Victorian Eye and Ear Hospital

Sir Charles Gairdner Hospital

St Vincent’s Hospital Melbourne

Sydney Adventist Hospital

Sydney Children’s Hospital

The Alfred Hospital Melbourne

University Hospital Geelong

Westmead Hospital

Women’s and Children’s Hospital

Non-profit research institutions

Baker IDI Heart and Diabetes Institute

Centre for Eye Research Australia

The Australian College of Optometry

CSIRO


Harry Perkins Institute of Medical Research

Hunter Medical Research Institute

Kinghorn Cancer Centre


Mater Research

Murdoch Children’s Research Institute

Peter MacCallum Cancer Centre

Parenting Research Centre

QIMR Berghofer

St Vincent’s Institute of Medical Research

Telethon Kids Institute

The Australian Centre for Behavioural Research in Diabetes

The University of Qld Diamantina Institute

Walter and Eliza Hall Institute of Medical Research

Westmead Millennium Institute

Industry

Abbott Actogenix AllerganBayerBristol Myers-SquibbEli LillyMedtronicNovartisNovo Nordisk Roche Sanofi

71collaborative institutions in

Australia



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7.3.2 International collaboration

International collaborations are important for maximising the global impact and relevance of Australian type 1 diabetes clinical research. Australian type 1 diabetes clinical researchers are globally recognised with strong collaborative networks internationally. Outside of formal clinical research networks, researchers collaborate on multinational clinical trials, and also leverage international expertise for other research projects. Active international collaborations reported by researchers are outlined below. Multinational clinical trials are not included here (see Section 3.4).

Universities

Albert Einstein College of Medicine

Cambridge University

National University of Ireland

National University of Singapore

Newcastle University

Oregon Health and Science University

University of California

University of Glasgow

University of Helsinki

University of Manchester

University of Pittsburgh

University of Toronto

University of Virginia

Yale University

Hospitals

Brigham and Women’s Hospital

Boston Children’s Hospital

Santa Maria Hospital

Sheffield Teaching Hospital

Sunnybrook Hospital

The Hospital for Sick Children

Non-profit organisations

Joslin Diabetes Centre

National Cancer Institute

St Joseph’s Healthcare

23international collaborating institutions



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7.4 Professional societies and groupsNetworking and collaboration can also be facilitated through professional societies and groups dedicated to a specific area of research or particular interest. These groups usually hold regular meetings where researchers can expand their network, share ideas and present their research. A marked proportion of type 1 diabetes clinical researchers in Australia belong to a professional society, with 42% of researchers surveyed participating in at least one society, and 21% belonging to both Australian and international societies.

Spotlight: The Australasian Paediatric Endocrine Group

The Australasian Paediatric Endocrine Group (APEG) was established in 1982 by Melbourne paediatrician Dr Norman Wettenhall. The association is an organisation of medical professionals dedicated to promoting and maintaining the highest standards of diagnosis and treatment of paediatric endocrine disorders, including type 1 diabetes.

APEG is the official body representing paediatric endocrinologists in Australia and New Zealand. The goals of the society are to promote research into paediatric disorders, collaboration and the free exchange of knowledge. APEG also funds and supports research projects and researchers.

The Australasian Diabetes Data Network (ADDN) was developed by APEG in partnership with the JDRF T1DCRN, providing a valuable resource of patient clinical data for clinicians and researchers in the field of type 1 diabetes (see page 63).



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Table 7.3: Australian professional societies

Name Purpose and relevance to T1D

Diabetes Specific

Australian Diabetes Educators Association (ADEA)www.adea.com.au

• To promote evidenced-based best practice diabetes education to ensure optimal health and well-being for all people affected by, and at risk of, diabetes

Australian Diabetes Society (ADS)www.diabetessociety.com.au

• To improve care and outcomes for people with diabetes

Australian Diabetes Councilwww.australiandiabetescouncil.com

• Aims to ensure those who have or are at risk of diabetes have access to the necessary care and support

National Association of Diabetes Centres (NADC) www.nadc.net.au

• To promote collaboration between specialist diabetes services and non-specialist service providers

• Collects diabetes data to improve standards, methods and models of diabetes care

Diabetes Relevant

Australasian Paediatric Endocrine Group (APEG) www.apeg.org.au

• To represent those involved in the management and research of children with disorders of the endocrine system including diabetes mellitus.

Endocrine Nurses Society of Australia (ENSA) www.ensa.org.au

• Provides a forum for continuing education and professional development for nurses working in the field of endocrinology

Cardiac Society of Australia and New Zealand (CSANZ) www.csanz.edu.au

• To facilitate training, professional development and improve medical practice to enhance the quality of care for patients with cardiovascular disease

• Not T1D specific but may be relevant in the context of cardiovascular complications

Australian Society for Medical Research (ASMR) www.asmr.org.au

• To foster excellence in health and medical research, expand the interface between basic science and clinical research, and promote community understanding and support

• Not T1D specific but encompasses all medical research

Australasian Society for Immunology (ASI) www.immunology.org.au

• To encourage, promote and support the discipline of Immunology in the Australasian region

Australian and New Zealand Society Of Nephrology (ANZSN)www.nephrology.edu.au

• To promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology

Australian Paediatric Society (APS) www.auspaediatrics.com.au

• To provide a comprehensive representation on issues that pertain to rural and regional child health and welfare

Perinatal Society of Australia and New Zealand (PSANZ) www.psanz.com.au

• Dedicated to advancing the theory and practice of perinatology and encouraging training and research in the field

• Not T1D specific but some involvement in T1D studies

Transplantation Society of Australia and New Zealand (TSANZ) www.tsanz.com.au

• To advance the science of transplantation and to foster collaboration with international and other regional societies interested in transplantation

• Not T1D specific but may be relevant in the context of islet, pancreas and kidney transplantation



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7.4.1 International professional societies

Several large, international professional societies exist which facilitate international collaboration and support researchers in the field of type 1 diabetes. Professional societies identified by surveyed Australian researchers are listed in Table 7.4.

Table 7.4: International professional societies

Name Objectives

Diabetes Specific

International Society for Paediatric and Adolescent Diabetes (ISPAD)www.ispad.org

ISPAD aims to promote clinical and basic science, research, education and advocacy in childhood and adolescent diabetes.

Immunology of Diabetes Society (IDS)www. immunologyofdiabetessociety.com/

IDS exists to bring together many strands of scientific endeavour with the goal of better understanding and treatment of type 1 diabetes. IDS is especially focused on clinical trials of new therapies.

Diabetes Technology Society (DTS)www.diabetestechnology. org/index.html

DTS’s mission is to lead collaborative efforts by experts to accelerate development of practical technology for treating, monitoring, diagnosing, and preventing diabetes and its complications.

European Association for the Study of Diabetes (EASD)www.easd.org

EASD aims to encourage and support research in the field of diabetes, the rapid diffusion of acquired knowledge and to facilitate its application.

American Diabetes Association (ADA)www.diabetes.org

ADA funds research to prevent, cure and manage diabetes, delivers services to hundreds of communities, provides objective and credible information and gives voice to those denied their rights because of diabetes.

The International Diabetes Federation (IDF)www.idf.org/

IDF aims to influence policy, increase public awareness and encourage health improvement, promote the exchange of high-quality information about diabetes, and provide education for people with diabetes and their healthcare providers.

Diabetes Relevant

The Endocrine Society (ENDO)www.endocrine.org/

ENDO works to foster a greater understanding of endocrinology among medical professionals and to promote the interests of all endocrinologists at the international and national scientific research and health policy levels of government.

International Pancreas and Islet Transplantation Association (IPITA)www.tts.org/ipita/home

IPITA is affiliated with The Transplantation Society, and aims to increase the utilisation of pancreas and islet transplantation across the world through education of and collaboration with diabetes care teams, administrators, payers, regulatory agencies, and organizations that coordinate donor pancreas allocation. IPITA also promotes clinical research including randomised clinical trials.



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Barriers to collaboratingBuilding strong, functional collaborations can be time-intensive and requires increased resources and management. Some issues relating to the development of collaborations that were reported by researchers are outlined below:

Funding for travelBuilding successful collaborations requires face-to-face meetings. The distance of Australia from major international research centres means researchers must make a deliberate effort to travel and build international collaborations. This is costly and time-consuming, and makes regular face-to-face meetings difficult.

Coordination between collaboratorsResearchers felt that they do not coordinate effectively with each other, and this can prevent maximisation of research strengths. National and global research priorities need to be identified and researchers need to coordinate their efforts to achieve research goals and avoid duplication.

Maintenance of international collaborationsThe lack of face-to-face interaction with international collaborators can mean these relationships are difficult to maintain.

Participation in large, international collaborative projects can result in a loss of money through difficulty in coordinating finances between countries. Some researchers prefer not to collaborate internationally for this reason.

Basic and clinical researcher disconnectThere is a divide between researchers conducting laboratory studies and clinical research. Basic and clinical scientists need to talk to each other more to identify patient needs and expedite research progress from pre-clinical studies to human trials.

Difficult to manage large numbers of collaborationsThere are a large number of potential collaborations in Australia, both within type 1 diabetes and in other areas of research. Developing strong, close relationships with existing collaborators should be a priority rather than seeking out more collaborations with no defined outcomes.



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7.5 SummaryAustralia’s geographical location can be a barrier to developing global collaborations, as extra time and resources are needed for the face-to-face interaction that is required to build good relationships. However, this has resulted in the development of an extremely cohesive network of closely collaborating experts. This unique research environment provides an opportunity for Australian researchers to coordinate with each other and accelerate research progress by concentrating their efforts on research priorities and sharing valuable resources.

Extending collaborative efforts internationally and across disciplines will provide Australia with additional opportunities to participate in research that is outside of our current focus, and maximise the global impact of Australian type 1 diabetes research.

Looking to the future Section 8


8. Looking to the future Clinical research is vital for transforming scientific discoveries into new therapies and treatments, ultimately benefitting the lives of people living with type 1 diabetes. Increasing type 1 diabetes clinical research must be prioritised to accelerate patient access to beneficial therapies, both in Australia and globally.


Section 8 Looking to the future

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8.1 OverviewAustralia is a leader in the ‘treat’ portfolio of clinical research, with a strong global presence in development of new technology such as the artificial pancreas to better manage blood glucose levels in established type 1 diabetes. There is also a strong focus on ‘prevent’ research, with studies investigating genetic and environmental factors that increase risk for developing type 1 diabetes. Australia does not have a strong focus on clinical research that investigates ways to preserve or restore beta-cell function after the onset of type 1 diabetes. One reason for this may be in identifying and recruiting eligible patients – our relatively small patient population poses a problem in recruiting sufficient numbers for these types of clinical studies. There are several large, international, multisite clinical trials that are targeted to new-onset type 1 diabetes, and increasing Australian participation in these trials would build Australian expertise in cure research and expedite Australian access to these therapies.

Australia has a strong foundation of basic laboratory research in type 1 diabetes; however the translation of basic research into clinical studies is a bottleneck that slows the progress of research and means many promising therapies do not progress to clinical trials. Further support and investment into this stage of the research pipeline will accelerate the delivery of clinical research in Australia. The high expense of clinical research, coupled with our small patient population, can limit the amount of research that can be undertaken in Australia, highlighting the necessity of coordination of our research priorities and consolidation of our resources. Overall, there is a need for a concerted, national effort to encourage Australian researchers to share and access the resources that are available in Australia, including databases, biobanks, and patient pools.

Australia’s type 1 diabetes research community is a close-knit, cohesive network of researchers dedicated to the common goal of curing and preventing type 1 diabetes and its complications. There are excellent opportunities to exploit our unique research environment to accelerate the progress of research from pilot studies to new treatments and therapies, and to increase the global impact of Australian research.



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8.2 AnalysisAnalysis of the current Australian type 1 diabetes clinical research landscape has highlighted Australian research strengths, identified pivotal opportunities to accelerate, expand and increase Australian type 1 diabetes clinical research, and exposed three broad areas of need within the development pipeline:

• Translational research: This ‘valley of death’ is relatively underfunded and many promising potential therapies do not progress through this stage to human clinical trials. Increasing access to relevant expertise and the resources necessary to co-ordinate and manage clinical research will facilitate the effective translation of research from the laboratory to clinical trials.

• Clinical trials: Early-phase clinical trials may not attract commercial funding due to the relatively high-risk of failure, yet the cost of these trials can easily exceed the funding available from non-commercial funders. In addition, the extremely high cost of later stage clinical trials in Australia can hinder commercial investment, particularly for type 1 diabetes which affects only a small proportion of the population.

• Clinical research resources: As there is a finite amount of funding available, targeted investment into underfunded stages of research can be amplified by investment into clinical research accelerators and enablers, such as clinical research infrastructure, databases and bio-resources. Many of these resources exist in Australia already, but are fragmented in individual research centres, and are often not available for wider use.


Section 8 Looking to the future

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Key recommendationsIncreasing patient access to new therapies and treatments is a priority both nationally and internationally. JDRF makes the following recommendations to maximise the delivery and impact of Australian type 1 diabetes clinical research.

Figure 8.1: Recommendations 1–5 addressing key stages along the research and development pipeline

1 Invest in new ideas and new researchers

Fund targeted grants for transformative projects that have the potential for high benefit. Current grant schemes tend to be risk averse and fund research in small, incremental steps. Targeted grants that encourage creative thinkers to pursue novel and exciting ideas should be implemented to drive the generation of new treatments and therapies.

Invest in career-support for emerging clinician researchers. A high proportion of clinician research time is unfunded, and there is little support for early and mid-career clinician researchers. Increased funding of research time for emerging clinician researchers will allow them to conduct their research and establish themselves in order to be able to attract further government or commercial funding.

Basic research


Clinical research



Funding$

$$


$$$

$

4 5

21 3



87

2 Accelerate research translation

Establish targeted funding schemes for bridging the ‘valley of death’ between innovative treatments developed in the laboratory and human clinical trials. Increased investment into schemes bridging this translational gap would enable researchers to gather proof-of-concept evidence and gain traction that would improve their ability to secure the large amounts of funding required for future clinical trials.

Increase infrastructure facilitating connection between basic and clinical researchers. Increasing collaboration between basic and clinical researchers, by putting in place clear mechanisms and procedures for connecting basic and clinical research within institutions will help to establish a research culture that recognises the necessity of research translation and has the tools available to maximise research progress.

3 Establish targeted clinical research funding schemes

Increase duration of clinical research grants. Clinical trials take at least 5 years to complete, yet current grants from major funding bodies last only 3–4 years. Targeted clinical research grants should have an increased duration of 5 years minimum to enable projects to be completed.

Increase the maximum amount of funding available for clinical research projects. Clinical research is much more expensive than laboratory studies, and current funding schemes are often insufficient to support a clinical project. Establish mechanisms to attract commercial or private funding such as a one-to-one matching scheme.

4 Connect Australian clinical research resources and infrastructure

Develop a national database of type 1 diabetes patients willing to participate in clinical research. There is a large resource of potential patient recruits in private practice that is currently underutilised. This resource could be tapped into by the establishment of an online, searchable registry of type 1 diabetes patients willing to participate in clinical trials. This database would facilitate location of eligible patients for a particular trial, and could also serve as a ‘living’ biobank.

Develop a ‘living biobank’. The national online database of type 1 diabetes patients could capture those willing to contribute to clinical research by participating in a clinical trial and/or by donating biosamples on demand. This would provide researchers with an instant resource of potential biosamples, and would circumvent problems associated with traditional biobanks such as incomplete clinical information, storage and maintenance, and complex ethics requirements.

5 Build targeted partnerships and collaborations

Invest in developing global collaborations. Building international collaborations is vital to position Australia as a global leader in type 1 diabetes clinical research. Due to the resource-intensive nature of developing international collaborations, efforts should be targeted to developing partnerships that will have the greatest impact. Investment into partnerships thatenable Australia’s participation in cure and new-onset trials will build research capacity in these areas, and increase Australian type 1 diabetes patient access to new therapies and treatments.

Build partnerships with industry to aid in commercialisation.Industry plays a critical role in the research and development process of new medical treatments andinterventions. Fostering a ‘big-picture’ research culture which includes commercialisation strategies should be a priority in type 1 diabetes research. This could be achieved by using commercialisation activities and partnerships to influence funding allocation and decisions, encouraging researchers to develop strategic partnerships in earlier stages of research.

Appendices and references


Appendices and references


Appendices and references Appendix 1

89

Appendix 1. ContributorsThe creation of this document was generously supported by a grant from the Macquarie Group Foundation. Many thanks go to the researchers listed below who donated their valuable time to participate in interviews and on-site visits.

Name Institute

Associate Professor Neale Cohen Baker IDI Heart and Diabetes InstituteProfessor Mark Cooper Baker IDI Heart and Diabetes InstituteAssociate Professor Jonathan Shaw Baker IDI Heart and Diabetes InstituteProfessor Merlin Thomas Baker IDI Heart and Diabetes InstituteAssociate Professor Mark Kotowicz Barwon HealthDr Chris Cooper Barwon HealthDr David Fuller Barwon HealthMs Heather Hart Barwon HealthDr Adam Roberts Barwon HealthMs Alana Sarah Barwon HealthMs Bree Sarah Barwon HealthDr Lyndell Lim Centre for Eye Research AustraliaProfessor Stephen Twigg Charles Perkins Centre/Royal Prince Alfred HospitalDr Monique Stone Children’s Hospital at WestmeadProfessor Ranjeny Thomas Diamantina InstituteAssociate Professor Shane Grey Garvan Institute of Medical ResearchProfessor Grant Morahan Harry Perkins Institute of Medical ResearchAssociate Professor Bruce King Hunter Medical Research InstituteDr Carmel Smart Hunter Medical Research InstituteProfessor Carol Pollock Kolling Institute of Medical ResearchProfessor Josephine Forbes Mater Medical Research InstituteAssociate Professor Anand Hardikar NHMRC Clinical Trials CentreDr Megan Penno Robinson Research InstituteProfessor Fergus Cameron Royal Children’s Hospital MelbourneAssociate Professor David O’Neal St Vincent’s Hospital MelbourneDr Tom Brodnicki St Vincent’s Institute of Medical ResearchDr Stuart Mannering St Vincent’s Institute of Medical ResearchAssociate Professor Helen Thomas St Vincent’s Institute of Medical ResearchDr Charles Czank Telethon Kids InstituteProfessor Timothy Jones Telethon Kids InstituteProfessor Graham Goodwin University of NewcastleDr Adrian Medioli University of NewcastleDr John Wentworth Walter and Eliza Hall InstituteProfessor Phillip O’Connell Westmead Millennium Institute


Appendix 2 Appendices and references

90

Appendix 2. Search terms used for online researchBiobanks and biospecimens

• autoimmune bank/collection/repository/samples

• cadaveric bank/collection/repository/samples • diabetes biobank• diabetes patient samples• diabetes tissue bank• DNA bank/collection/repository/samples• eye/kidney bank/collection/repository/samples• kidney/eye repository/bank/samples/collection• organ donors • paediatric bank/collection/repository/samples• specimen bank/specimen sharing• stem cells bank/collection/repository/samples

Clinical trial networks

• artificial pancreas consortium/network• autoimmune/immune therapies clinical

research network• clinical research consortium/network• diabetes clinical network• diabetes research network• eye/cardiovascular/kidney/neuropathy/

ophthalmic/ consortium/network• microbiome research network/consortium• paediatric research network/consortium• translational research network/consortium• transplant research network/consortium• type 1 and 2 diabetes clinical research

Databases

• autoimmune database• clinic/clinical database• clinical trials database• data repository• diabetes database• genetic database• paediatric database• patient/hospital database• eye/cardiovascular/kidney/nephropathy/

neuropathy/retinopathy/ database

Professional societies

• diabetes society• eye/cardiovascular/kidney/neuropathy/

ophthalmic/renal/ society• immunology society• microbiome society• paediatric society


Appendices and references Appendix 3

91

Appendix 3. Major multisite clinical projects in Australia from 2005–14Adolescent Diabetes Intervention Trial (AdDIT)

AdDIT is a multisite, international trial investigating whether the use of cholesterol-lowering and blood pressure-lowering drugs in adolescents with type 1 diabetes improves short-term markers of cardiovascular complications. www.addit-trial.org

Australasian Diabetes Data Network (ADDN)

ADDN connects clinical data from thousands of young people living with type 1 diabetes captured from five Australian paediatric specialist centres on a single purpose-built database.www.addn.org.au

Australian Childhood Diabetes DNA Registry (ACDDR)

The ACCDR collected DNA samples across Australia from the saliva of over 1800 family trios of a child with diabetes and their biological parents in order to facilitate the identification of genes affecting the risk of developing type 1 diabetes.www.acddr.org.au

Australian Islet Transplantation Program (ITP)

The Australian ITP is an initiative that funds the transplantation of donor islets into people with type 1 diabetes, as well as research studies related to improving transplantation outcomes. www.ncbi.nlm.nih.gov/pubmed/23668890

Environmental Determinants of Islet Autoimmunity (ENDIA)

ENDIA is a multisite Australian study that will follow first-degree relatives of people with type 1 diabetes from before birth throughout childhood and investigate the interaction of environmental and genetic factors in the development of islet antibodies.www.endia.org.au

A Trial in Adults With Type 1 Diabetes Mellitus Evaluating the Effects of Fenofibrate Versus Placebo on Macular Thickness and Volume (FAME 1 EYE)

FAME 1 EYE is an Australian study that investigates the ability of the blood lipid-lowering drug fenofibrate to prevent progression of eye damage in adults with type 1 diabetes.www.researchdata.ands.org.au/fame-1-eye/455373


Appendix 3 Appendices and references

92

Intranasal Insulin Trial (INIT II)

INIT II is an Australian clinical trial investigating the use of intranasal insulin for the prevention of type 1 diabetes in individuals susceptible to developing type 1 diabetes.www.stopdiabetes.com.au

Predictive Low-Glucose Suspend Study (PLGS)

PLGS is an Australian study coordinated by the Telethon Kids Institute in Perth, investigating the use of a feature on insulin pumps that can predict an upcoming hypoglycaemic episode and suspend insulin delivery before it occurs.www.telethonkids.org.au/our-research/projects-index/p/predictive-low-glucose-management-study/

Reducing with Metformin Vascular Adverse Lesions in type 1 diabetes (REMOVAL)

REMOVAL is an international, multisite trial investigating the use of metformin, a drug commonly used in type 2 diabetes, to improve cardiovascular function in adults with type 1 diabetes. The Australian substudy is also investigating the pharmacological mechanism for the effects of metformin.www.clinicaltrials.gov/ct2/show/NCT01483560

Trial to Reduce IDDM in the Genetically at Risk (TRIGR)

TRIGR was an international, multisite clinical trial that investigated whether hydrolysed infant formula compared to cow’s milk-based formula decreased risk of developing type 1 diabetes in children with increased genetic susceptibility. www.trigr.org

TrialNET

TrialNET is an international network of researchers who are exploring ways to prevent, delay and reverse the progression of type 1 diabetes. TrialNET coordinates clinical studies such as Pathway to Prevention that is investigating how various antibodies correlate to the risk of developing type 1 diabetes.www.diabetestrialnet.org

Type 1 Diabetes Genetics Consortium (T1DGC)

T1DGC is an international consortium of researchers that seeks to identify genetic markers that relate to the risk of developing type 1 diabetes and its complications. T1DGC also established a renewable resource of DNA from thousands of people with type 1 diabetes and their families.www.niddkrepository.org/studies/t1dgc


Appendices and references References

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