TABLE OF CONTENTS
1. Executive Summary
2
2. Background
3
3. Rationale for a Specific Paediatric Network
6
4. Proposed Network Structures & Functions
9
5. Benefits
13
6. Requirements for Establishing the Network
15
7. References
16
8. Appendices
17
Appendix 1, SWOT analysis
17
Appendix 2, Support for the proposed Treatments for Children
Research Network
20
Appendix 3, Proposed network process & functions for
Investigator-initiated study proposals
25
Appendix 4, How the Network’s Services will enhance industry
sponsored trials
28
Appendix 5, Five year financial projections
31
1
Treatments for Children Research Network - Australia
1. EXECUTIVE SUMMARY
Up to 81% of drugs prescribed for children have never been tested in the paediatric population
and child health-care is based on extrapolations from adult data (Tan, 2003). As a result,
product labelling frequently fails to provide directions for safe and effective use in paediatric
patients. (FDA, 1998). The regulatory authorities in Europe and the USA have recognised the
need for more clinical trials in children and introduced legislation to act as a strong incentive for
greater investment in more paediatric trials. As a result pharmaceutical companies worldwide
are seeking to conduct more clinical trials in the pediatric population.
Australia could exploit this market opportunity by attracting the increased investment put into
these trials to our country. This would provide great benefit to children, but also provide benefit
to the Australian economy, the clinical research sector, the broader health care sector and the
wider community. Here in Australia, we have world class paediatric specialists, substantial
expertise and experience in paediatric research, an equitably accessible health care system
with good follow-up, an efficient regulatory approval process, and a genetically diverse
population. Unfortunately, these strengths are not well leveraged due to the lack of clinicalresearch-enabling infrastructure in Australia. An absence of patient referral networks and
inefficiencies in approval for multiple sites present obstacles to conducting clinical studies in
Australia. Working with children and adolescents adds an extra level of complexity to the
challenge. A national paediatric clinical research network could overcome these barriers and
increase our capacity to maximise the opportunities for engagement in clinical research in
Australia.
This submission enthusiastically recommends a National Paediatric Clinical Research Network
as a solution to both the paucity of evidence-based health care for children and the current
deficiencies of clinical research infrastructure in Australia. Such a network would increase the
capacity and cost-effectiveness of conducting both industry-sponsored clinical trials and
investigator-initiated studies, attracting investment. The network will support paediatric studies,
focusing on randomised controlled multicentre trials but also enabling other well-designed
studies.
The Network would have a core Co-ordinating Centre and Local Study Support Units at major
paediatric centres across Australia, supporting study implementation and recruitment. The core
co-ordinating centre would be responsible for governance and central management of network
endorsed studies across the network sites. The network will integrate existing discipline-based
paediatric research networks into a more efficient and cohesive structure.
The Network will require government funding for establishment and for some elements of the
ongoing operational costs. Revenue will also be acquired through sponsors and from successful
investigator driven study grants.
Overall, the proposed network will require ~$1.6M increasing to ~$1.8M over 5 years from
Australian Federal and State Governments. This additional commitment will allow the
government’s current investment into clinical study infrastructure to be maximised.
Australia will benefit from greater investment in paediatric clinical trials, since a coordinated
multi-centre approach to paediatric clinical research will make Australia a cost-effective trial
location through:
• Increasing the recruitment capacity for studies
• Increasing the speed and efficiency of initiation and completion of studies
• Increasing the quality of design and conduct for studies
Additional key benefits of the proposed Network include:
• Greater access to new, evidence-based treatments for children and adolescents
• Increased knowledge driving disease treatment in children and adolescents
• Increased level of academic activity in Australian Children’s Hospitals and affiliated
Research Institutes and increased research capacity in smaller and regional centres
• Increased capacity to interact effectively with global initiatives and networks
2
2. BACKGROUND
Healthcare professionals agree that a child cannot be treated as a mini-adult, nor an
adolescent as a young adult. They differ from adults in their physiology, developmental
profiles, psychology and the diseases they suffer. Children’s dynamic development,
especially during periods of rapid somatic growth, makes them more susceptible to
many environmental exposures, including pharmaceuticals. There are many examples
of children and adolescents responding dramatically differently to medications and
treatments compared with adults. They are also a heterogeneous group; Children of
different ages absorb, distribute, metabolise and excrete drugs differently. All of these
factors mean that adult studies are not readily transferrable to paediatric populations.
Yet many of the drugs routinely prescribed for young children have not been tested in
children; the doses being extrapolated from studies in adults or older children (Holt et
al., 2004). In fact, a review of the data supplied with approximately 1500 drugs found
that 81% of drugs that are used in babies less than 1 month old, and 72% of drugs that
are in children between 6–12 years old, contained inadequate dosing information for
that age group (Tan, 2003).
Ineffective and unsafe drugs and drug doses are given to children every day in
Australia and the nation’s health benefit scheme is paying for it. Statistics from the US
Food and Drug Administration (FDA) demonstrate the dire consequences of this
situation; between 1997 and 2000, the FDA received over 7000 adverse event reports
of potential side-effects concerning children younger than two years of age; 11%
proved fatal and 61% were serious: resulting in death, disability, congenital abnormality
or hospitalization (Greener, 2008).
This inequity has evolved due to a number of reasons. Conducting clinical studies with
children and adolescents to answer questions of treatment safety and effectiveness is
more arduous than in adults. The reasons for this include difficulties with recruitment
due to the small numbers of participants eligible at any one site, especially for rare
diseases. Age appropriate environments and equipment must be considered, as well
as the tendency for compliance and cooperation to wax and wane in this age group.
Additional ethical constraints apply when obtaining consent for research on children
and adolescents (the parents must be informed and willing and so must the young
participant). The appropriate outcome measures also change with growth and
developing maturity, adding complexity to protocol design. Confounding these more
operational challenges is the fact that the adult market is more returns rich and hence
more attractive to the therapeutics industry for investment.
Both the US Food and Drug Administration (FDA) and the European Medicines Agency
(EMEA) have passed new regulations that necessitate paediatric studies when a
product is likely to be used in children, given the product’s mechanism and properties.
Many stakeholders hope to see similar regulatory changes in Australia (the Therapeutic
Goods Administration has not yet mandated that pharmaceutical and medical device
companies conduct paediatric clinical trials before issuing market approval, even when
the approved indication is prevalent in this age group).The FDA can offer extended
patent protection and marketing exclusivity in return for conducting the paediatric
studies. By March 2008, the FDA had granted exclusivity for 150 drugs and requested
842 studies enrolling more than 49,000 children—most of which are new indications of
existing drugs (Greener M, 2008). Since July 2008, companies that want to market a
new medicine in the European Union (EU) must show results of paediatric studies and
child formulations, unless it can be demonstrated that the indication does not exist in
children. After approval, a drug supported by paediatric studies receives an extra six
months of patent protection in the EU (Greener M, 2008).
3
These initiatives provide strong incentives for companies to invest in more paediatric
trials, increasing the demand for favourable countries in which to conduct studies.
Pharmaceutical companies operating in Australia have noted that these provisions will
now increase investment in paediatric research for new medicines. (Paediatric
Medicines Industry Scoping Study Final Report – May 2009).
Australia is in a great position to exploit this growth export market by attracting
investment from drug development companies across the globe. We have highly
trained and respected paediatric clinicians with reliable follow-up; a paediatric research
community with extensive expertise and specialised facilities and large paediatric
tertiary hospitals in most states that are often co-located with medical research
institutes and affiliated with universities. We also have a large multicultural population
which is much more attractive for conducting clinical trials than a homogenous
populace that may have unique genetic or cultural pre-dispositions which bias study
results. Relative to many countries, we have a rapid notification process for obtaining
approval to use unlicensed therapeutic goods for a clinical trial. Australia is on the cusp
of a substantial opportunity with both real economic benefits and far-reaching health
benefits for children and young people.
Regrettably, we may miss the boat. Competition from countries developing more
favourable operating environments is discouraging investment in Australian sites for
clinical research. Specifically, Australia is losing its cost-competitiveness with regards
to recruitment rates, quality of research conduct and the time it takes to commence a
study (including the required approvals).
Industry representatives in Australia have identified that there is a need to improve
paediatric research infrastructure to encourage investment. A consultant engaged by
the Department of Health and Aging conducted an ‘Industry Scoping Study’ involving
interviews with 21 pharmaceutical manufacturers and/or marketers operating in
Australia. The purpose of the industry scoping study was to explore, define and
quantify barriers to the pharmaceutical industry in the registration, listing and marketing
of medicines and formulations suitable for paediatric use in Australia.
The findings of the study, presented in the Paediatric Medicines Industry Scoping
Study Final Report (May2009), summarise the views of the pharmaceutical industry: A
deficient infrastructure for paediatric studies was seen to be the most important
logistical barrier, and was rated by several global companies as more important than
regulatory barriers, impacting heavily on the ability of pharmaceutical companies to
register medicines suitable for paediatric use.
Drawing on findings from the consultation, Figure 1 below represents industry’s view of
the research related factors that must be present and combined to ensure eventual
registration and/or listing of a medicine.
Figure 1 - The factors required to be present for paediatric research.
Paediatric research Paediatric research is adequately funded Paediatric research workforce is adequately skilled Specialist network enables knowledge sharing All stakeholders have input into decision‐making (researchers, clinicians, regulators, funders, patients/parents and industry) Process exists for facilitating recruitment without compromising informed consent or ethical standards Adapted from the Paediatric Medicines Industry Scoping Study, May 2009, p25
The report suggests that industry representatives in Australia support the concept of a
paediatric clinical research network.
4
Australia does not have a strong history of government investment into paediatric clinical
research. While total NHMRC funding for all clinical trials has increased substantially from
2000-2009, the rate of increase has not been as great in paediatric clinical trials; the
percentage of total funding dedicated to child health has dropped from 26% of the total budget
for clinical trials and related issues in 2000 to 15% in 2009 (see Figure 2 below). While the 015 age group alone makes up 19.1% of the Australian population (ABS, 2009).
$60,000,000
$50,000,000
$40,000,000
All Clinical Trials Related
Issues
$30,000,000
Child Health
$20,000,000
$10,000,000
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
$0
Figure 2 NHMRC funding for paediatric clinical trials compared to overall funding
for clinical trials between 2000 and 2009.
Deficiencies in child health care will have major repercussions for the future economic
well-being of the nation. For example, childhood and adolescent obesity, diabetes,
asthma and mental health issues will persist into adulthood. A paediatric clinical
research network that enables a developmental approach to improving long term health
outcomes will optimise health outcomes across society whilst concomitantly improving
the operating environment for industry and clinical investigators alike.
An analysis of the strengths, weaknesses, opportunities and threats characterising the
Australian operating environment for paediatric research is attached (Appendix 1). Our
SWOT analysis includes factors that are the focus of the current Clinical Trials Action
Group whose call for suggestions to help improve the current operating environment
has inspired this submission. The proposed ‘Treatments for Children Research
Network’ described in this submission will capitalise on the listed strengths and
opportunities and address the listed weaknesses, in whole or in part.
5
3. RATIONALE FOR A SPECIFIC PAEDIATRIC NETWORK
Multicentre studies are required to involve sufficient participants in a clinical study and
ensure broader clinical applicability. The value of national networks for facilitating
clinical research is widely recognised, and some of the benefits are specifically
identified by the Australian Pharmaceutical Industry Strategy Group (PISG), in their
final report (December 2008) as follows:
“Establishing a number of national patient referral networks in key therapeutic areas would provide: • ‘rapid‐access, single point of access’ to comprehensive healthcare research infrastructure within Australia • rapid patient recruitment and delivery of high quality data for clinical studies across a range of medical conditions, including paediatrics, cancer, lung disease • greater patient access to clinical studies (especially for severe and life threatening conditions) through more effective study referral patterns in the health system • accelerated product development through successive well established collaborations.” Besides the specific reference to paediatrics above, the PISG report also describes the
initiatives of the UK Clinical Research Network, which consists of a managed set of six
Topic Specific Clinical Research Networks. One of these six networks is specifically for
paediatric research – the medicines for children research network (MCRN:
www.mcrn.org.uk).The size and breadth of the MCRN portfolio of industry studies has
considerably exceeded expectations, since it began operating in 2006. The following
graph shows the growth of their portfolio through cumulative totals of both industry and
publicly funded studies adopted. Many other studies are in the pipeline, but have not
yet been adopted.
. Figure 3 Cumulative totals of studies adopted by the MCRN (up to Nov 2009)
6
A number of other countries have also recognised the need for, and value of, national
paediatric specific clinical research networks, for example:
• Germany (PAED-net, 2002) www.paed-net.org/
• The Netherlands (MCRN, 2006) www.mcrn.nl/
• Belgium (BPDN, 2004) www.pediatrie.be/pediatricdrug.htm
• Finland (FINPEDMED, 2007) www.finpedmed.fi
• France (RIPPS, 2008) www.ripps.eu/site/defaut/
• USA (PPRU) www.ppru.org & (NRN) neonatal.rti.org/
We proposed a dedicated paediatric network in Australia in consideration of the need
to address the specific challenges of paediatric clinical research. Challenges specific to
paediatric studies which would be addressed most effectively in a specific paediatric
network include:
• Managing the ethical issues of studies in children and adolescents. Addressing
matters such as judging capacity for consent and developing age-appropriate
information materials will prevent ethics approval delays.
• Researching the unique pharmacokinetic and pharmacodynamic characteristics
of medicines in the paediatric population.
• Consideration of the outcome measures most appropriate to paediatric studies.
Many outcome measures used in adults are not suitable for children or
adolescents or they are irrelevant because of mixed age and maturity within the
paediatric population. Studies extending over several months or years must
consider the effect of the developing participant.
• Managing governance and funding issues particular to paediatric centres and
studies. For example, children must be accompanied by their parents or
guardians and the imposition on the whole family must be considered.
• Consideration of paediatric-appropriate medical procedures in studies.
A simple blood test can be very traumatic for some children and paediatric
trained nurses and a child-friendly environment are critical.
• Consideration of paediatric-appropriate formulations in studies. The most
convenient formulation for adults may be unsuitable or intolerable for children.
• Follow-up of children in paediatric and neonatal trials may extend over many
years to achieve meaningful outcomes. Appropriate funding mechanisms need
to be developed to accommodate for this necessity.
• Managing consent and accommodating mental and social change during
pubertal change and adolescence. Designing and managing clinical research
with this age group, when the challenges can be even more pronounced,
requires a sub-set of specialty skills.
Dedicated paediatric sites will also increase local skills and resources such as:
• Recruitment officers who are experienced in recruiting children, young people
and families
• Child- and adolescent-friendly facilities and family-friendly facilities
• Specialised equipment for procedures such as resuscitation and blood drawing
in children
• Improve delivery of health care services to children in smaller and regional
centres through training of staff in paediatric procedures
The European and US paediatric clinical research networks listed above successfully
manage both sponsored and investigator-initiated studies. The proposed Network is
similar, as there are extensive benefits to be gained from coexistence of Industry and
Investigator-driven studies in a specialised network:
7
The community of paediatric investigators and research institutions will effectively
support and engage with a network that contributes to investigator driven studies and
patient-centred research. The infrastructure associated with an investigator-supported
network, such as national patient referral networks, will provide the required capacity
for industry sponsored studies. This capacity for highly innovative studies and
strategies aimed at disease prevention and health delivery research is also important to
industry: Whilst these areas are rarely the subject of industry trials, they certainly fuel
the industry development pipeline.
Industry-sponsored study activity will increase exposure of the research workforce to
clinical studies and standards of conduct as well as allowing employment of
investigator support staff on a sustainable basis, which in turn improves the capacity for
investigator-driven research.
The services offered by the Network for Industry sponsored studies include:
• Single access point for nationwide facilities, investigators, experts
• Expert Advice on study concepts and protocols
• Feasibility assessments
• Compilation and triage of ethics and governance submissions
• Standardised costing templates for site budget
• Facilitation of recruitment
• Training and support for investigator teams across Australia
The scope of the proposed Network is as follows:
•
•
•
•
•
•
Paediatric studies only
Focus on Randomised Controlled Trials, especially multi-centre trials but also
supporting other well designed studies such as observational, life-course and
health services research studies.
Phase I, II, III & IV clinical trials
Both investigator-driven & industry-sponsored studies
Across all therapeutic areas in paediatrics
Pharmaceutical therapies & other non-drug interventions including
physical/rehab therapies and devices
Objectives of the proposed Network:
•
•
•
Strengthen the evidence base for treatment of all children and adolescents
through clinical research
Improve the Australian operating environment for paediatric clinical trials
sponsored by industry
Increase the quality and quantity of Australian investigator-driven paediatric
clinical studies
8
4. PROPOSED NETWORK STRUCTURE AND FUNCTIONS
This is a joint proposal from senior paediatric clinical researchers across Australia. The
consultation process is ongoing, and has strong support and enthusiasm from a broad
range of Australian leaders in paediatric clinical research, including many with
prominent roles in existing clinical research collaborations and networks. Support has
been forthcoming from five states and territories and a spectrum of therapeutic areas.
The concept of developing an Australia-wide paediatric trial network has been
discussed by the major paediatric centres for some time. Appendix 2 contains a list of
the people who have contributed to this proposal and are prepared to be involved in
the proposed Network and/or support its development.
There are several pre-existing disease specific paediatric trial networks in Australia and
a variety of informal, collegial consortia and collaborations. These are of varying size,
structure and function; however they are generally not well enabled by infrastructure.
The proposed Network would link with these existing networks in ways that best
provide mutual support. As described in section 4c, Clinical Expert Groups (CEGs) are
a crucial element of the proposed Network and existing groups of clinician researchers
will naturally form an important basis for the establishment of these groups.
Appendix 2 contains a list of groups that have been consulted on the concept of the
Network and have stated their intent to be involved:
The groups collaborating on this submission have conducted detailed reviews of the
structure and functions of existing Australian and overseas networks and clinical trial
facilities, and appraised their appropriateness for the Australian paediatric context.
Several members of the group travelled to the site of the UK MCRN in Liverpool in
October 2009, prior to the announcement of the Trials Action Group, where they
consulted with the managers and employees of that network regarding establishment
and coordination of the network’s activities.
The proposed model for the Treatments for Children Research Network is an
adaptation of the UK Medicines for Children Research Network fitted to the Australian
context and existing capabilities. The Network would have a core Coordinating Centre
and Local Study Support Units (LSSU) at each hospital or affiliated research institute.
Figure 4 Representation of the proposed Network
9
The proposed model (including details of key functions, structures, and relationships)
and projected costs are indicative at this stage.
Description of the elements of the proposed network:
a. NETWORK COORDINATING CENTRE:
The network coordinating centre will manage the network’s operations for industry
sponsored and investigator initiated studies, as well as fulfilling strategic functions.
The Network Coordinating Centre will take recommendations from an advisory
committee and report, via a director, to a governing body. This governing body will
report to the relevant ministries.
The functions of the Network Coordinating centre will include:
• Liaison with industry and contract research organisation representatives and
coordination of feasibility assessments, budgets and agreements directly with
investigators and others with relevant expertise
• Deciding whether each trial can be adopted into the Network
• Coordination and oversight of Local Study Support Unit (LSSU) activity for trial
start-up, conduct and closure (see section 4b for an overview of LSSUs)
• Coordination of Clinical Expert Groups (see section 4c for an overview of CEG)
• Coordination of consumer liaison and input (See Box 1)
• Management of accounts (invoices and payment coordination for investigators)
• Coordination of patient referral network website and initiatives
• Development and implementation of Network SOPs and guidance materials
• Development and implementation of standardised training
• Coordination of initiatives to foster collegiality amongst investigator teams on
network adopted studies
An additional arm of the Network Coordinating centre will operate in the development,
set-up and conduct of Investigator-initiated trials. These services will not be utilised by
industry-sponsored trials, as the trial development, management and data processing
will be undertaken by the sponsoring company or a contract research organisation.
Functions specific to the Investigator-initiated Trials Arm of the Network Coordinating
Centre include:
• Allocating resources and teams of network staff to collaborate with proposing
investigators to develop proposals into funding applications, then (if funded) into
protocols, implemented multicentre trials and final publications.
• Dedicating a Trial Manager at the network coordinating centre to manage the
set-up and conduct of each trial across the multiple investigator sites.
• Recruiting and resourcing appropriate Independent Data Safety and Monitoring
Boards
• Data for each trial will be managed centrally, through a Trial Data Management
System.
See Appendix 3 for further detail regarding the process for Network involvement with
investigator initiated trials, from proposal to dissemination.
The coordinating centre will have a small core administrative staff based at a location
decided by tender. Additional staff will be spread across institutions, with staff in at
least Melbourne and Sydney from the outset, to leverage existing capacity. These staff
may be employed at a full or fractional rate by the Network or their services acquired
pro rata. When engaged in Network activity all staff will operate according to the
Network’s standard operating procedures (SOPs) and systems, and Sponsor’s SOPs
where agreed.
10
Box 1 - Network-Coordinated Consumer Involvement
The Network will be committed to involving consumers in health related research,
including children and young people with experience of health conditions or health
settings, parents/carers with experience of, or interest in, health conditions and/or health
settings and organisations that represent children’s and young people’s interests.
The network consumer liaison officer will develop and implement network-wide strategies
and policies on consumer and community participation in research.
It is planned that the Network Coordinating Centre will link with existing groups involved
with consumer liaison.
Involving children, young people and parents will be important because:
• It provides an opportunity for people to have a say in research that may have an impact
on their health, or the health of others; It helps to ensure the issues that are researched
are those that are important to children, adolescents and families; Consumer input can be
crucial for the design of studies
and medicines that are acceptable to children,
adolescents and their families; and the outputs of studies are more likely to become
known to consumers, and hence achieve greater impact
Proposed consumer liaison activities include:
• Setting up a young people’s advisory group
• Involvement of parents/carers as members of clinical expert groups (CEGs)
• Maintaining a consumer database of people willing to be contact and consulted
regarding the network’s research activities
• Promoting research and raising awareness of the network to children and families
in each region, including at schools and public events
• Production of a child/family friendly website
• Production of educational information for consumers
• Coordinating and participating in consumer engagement events and existing
consumer and patient groups, such as support groups
• Engaging in knowledge translation activities, to disseminate relevant research
results to consumers and the wider public
b. LOCAL STUDY SUPPORT UNITS (LSSU):
Local Study Support Units will be located across Australia, in regions with investigator
sites relevant to the network, including one in the vicinity of each paediatric hospital.
LSSUs are proposed in Sydney, Melbourne, Adelaide, Perth, Darwin, Brisbane and
Newcastle at the outset. It is anticipated that large states like NSW and Victoria will
eventually have 2-3 centres.
Each LSSU will support investigators across multiple departments and local institutions
to conduct trials.
The personnel available within each unit will include:
• Trial Administration Coordinators, responsible for compiling ethics and
governance submissions; maintain database of potential local investigators for
future trials.
• Recruitment Officers, responsible for coordinating recruitment efforts for each
trial at the sites; actively assisting the recruitment of participants; engaging in
local patient referral network activities
• Investigator Support Staff (Study Coordinators, Study Nurses and/or Research
Assistants), available for secondment to investigator teams when the existing
research support team in an investigator’s department is insufficient for the
conduct of a network adopted trial. Alternatively, the Network Coordinating
Centre can provide guidance to investigators on the recruitment of such support
staff. Support staff will be involved in participant recruitment, conducting trial
visits and procedures with participants, data collection, sample collection and
other trial tasks delegated by investigators.
11
The specific locations for LSSUs will be decided by tender, to ensure that the selected
groups have the best capacity to leverage in this function. It is anticipated that in some
cases LSSUs and/or some of their staff will be part of existing local clinical research
support structures at paediatric hospitals and affiliated research institutes. LSSU staff
would be employed by the host institution and services reimbursed by the Network.
All sponsored studies adopted by the network will engage LSSUs and the Network
Coordinating Centre will oversee the performance of all LSSUs.
c. CLINICAL EXPERT GROUPS (CEGs):
A set of clinical expert groups will be established and coordinated, representing various
paediatric specialty areas of clinical research.
Each group will be comprised mainly of paediatric clinician researchers. Other
members may include, as appropriate, a biostatistician, formulations chemist, clinical
pharmacologist, allied health specialists, health economist or consumer (parent)
representative.
The roles of each CEG are to:
1. Identify and define research priorities in the specialty area.
2. Collaborate as a group to develop study proposals to address important
clinical questions that are of relevance to children and present these to the
Network Coordinating Centre for adoption and development.
3. Ensure that studies proposed to the Network by investigators are acceptable
(in light of research priorities) and feasible, by reviewing proposals and
providing constructive feedback to proposing investigators.
4. Have members contribute to quick turn-around feasibility assessments for
industry sponsored studies, as well as responding to requests for information
and advice.
5. Ensure the research load on any one patient group is not too heavy and that
trials offering the most promising treatments for participants are prioritised
Each group will have an appointed chair and an administrative coordinator will be
common to all groups. The members will be appointed from across Australia and will
meet mainly via teleconference. The network coordinating centre will support the CEGs
through administrative and secretarial costs, and additional financial support will be
sought from charities and professional associations. It is anticipated that pre-existing
disease-specific networks, collegial groups and professional bodies will form the basis
of many CEGs.
The proposed clinical expert groups for the Network could include:
● Allergy
● Nutrition & Obesity
● General Paediatrics
● Infectious Diseases
● Kidney Disease
● Mental Health
● Neuromuscular
● Oncology
Diabetes and Endocrinology
Neonatal & Perinatal Medicine
Indigenous Health
Immunisation and vaccine
Rheumatoid and Inflammatory
Respiratory, Sleep Medicine & Cystic Fibrosis
Emergency medicine, anaesthetics, stroke & intensive
care
●
●
●
●
●
●
●
12
5. BENEFITS
Companies sponsoring clinical trials will benefit from increased cost
effectiveness of conducting paediatric clinical trials in Australia, via:
•
•
•
Enhanced speed of start-up, through a convenient and efficient single access
point to the facilities and investigators encompassed by the network, prompt
and reliable feasibility assessments and triaged scientific, ethics and
governance approvals.
Enhanced recruitment, through actively enhanced recruitment efforts and the
coordination of patient referral networks increasing participation in trials.
Enhanced quality through greater access to relevant skills and expertise, as
well as Network management and oversight of trial conduct.
The specific ways that the Network’s functions will improve the Australia operating
environment for paediatric industry studies are detailed in Appendix 4.
Box 2 provides some examples of the positive impact of the UK MCRN on industry
studies, demonstrating the potential benefits of the proposed Network to Australian
Industry.
Box 2
The MCRN Experience: Study Start-up times
ƒ
ƒ
ƒ
Case study: In a large, multicentre neonatal trial, the time from site open to first infant
recruited was around a month earlier in MCRN supported sites, compared with sites
without MCRN local support units (LRN), as depicted in Figure 5 below:
Figure 5 Time to first infant recruited in supported Vs unsupported sites
Of the first 26 feasibility assessments, MCRN conducted 22 within 10 days. A survey of
companies indicated that all found the feasibility assessments useful or very useful.
Positive feedback has been received from companies regarding study-start-up support.
The MCRN Experience: Recruitment Rates
ƒ
ƒ
For studies run in both MCRN supported sites, and sites without MCRN support (no
MCRN local support unit), recruitment rates have been consistently higher in the MCRN
supported sites.
Of the 19 MCRN supported industry studies that have finished recruiting, 12 (63%) met
or exceeded their recruitment targets and 4 others were very close to reaching their
targets. Recruitment to the remaining 3 was limited to 12.5-44% due to studies ending
early or lack of clarity over recruitment dates and targets.
13
Australian children and adolescents will benefit from
• Access to safer treatments, safer doses, more effective treatments and new
medicines at the earliest possible opportunity
• Evidence based clinical care leading to better health outcomes
• A better understanding of the development of complex diseases that are
increasing in prevalence (diabetes, mental health, asthma)
Clinical researchers will benefit from
• Access to consistent, current and comprehensive clinical research training that
meets international standards for good clinical practice
• Quality research proposals developed through collaboration and expertise
which will increase the chance of project funding
• Stronger collaborative environment fostering the development of new research
ideas; cross-pollination of research from different disciplines
• Increased capacity to interact effectively with global initiatives and networks, in
clinical trials generally and paediatric drug trials specifically
• Easier access to facilities and specific expertise such as statistical expertise
and health economic assistance
• Access to paediatric trained clinical research support staff thus enabling timepoor clinicians to participate in research
• Access to larger populations for study
o Enable the study of uncommon but high burden diseases
o Identify uncommon but high burden outcomes for common diseases
o Faster answers to important clinical questions in common diseases
• Faster recruitment
• Easier and cheaper approval processes for governance and ethics
• Efficiency of clinical trial management due to standardised and streamlined
processes and appropriate delegation
University and research institutes will benefit from
• Greater and more efficient infrastructure to support sponsored studies and
investigator driven studies and more efficient use facilities
• Better leverage of research project funding
• Opportunity to pursue and commercialise translational research projects
Hospitals will benefit from
• Academically attractive hospital environment attracting higher quality clinicians
from overseas and retaining local talent
• Increase in evidence-based medical practice which will lead to better health
delivery outcomes and a reduction in adverse events
• Better risk management due to adoption of good clinical practice standards
• Better leveraging of the investment that some hospitals have already made into
clinical research infrastructure
• The enabling of high quality locally relevant health care delivery research
Australian public/government will benefit from
• A substantial boost in Australia’s international competitiveness as a destination
for sponsored paediatric clinical trials, increasing research and development
investment by sponsoring companies, which will bring benefits, including
employment, to the Australian economy
• The paediatric network could be used as a pilot for a similar adult clinical trials
network
• Long term reduction of health costs; “healthy start, healthy future”
14
6. REQUIREMENTS FOR ESTABLISHING THE NETWORK
COSTS
A financial model for the TCRN is included as Appendix 5. The model assumes a
year on year increase in clinical study activity over the first five years. The main cost
driver for the model proposed is labour. To keep the costs minimised, it is proposed to
initiate the national network with the minimum number of staff and increase network
employees in line with the increase in activity. Additionally, many positions will begin
with minimum hours and build up to full-time equivalents over time. The growth of the
network is predicted to move from ~20 full time equivalents to ~60 after five years.
These estimates are based on the growth in activity enjoyed by the MCRN UK network
and the number of staff they have required in their central coordinating centre and
regional study units.
The network will require government funding for the establishment of the network and
for some elements of the ongoing operational costs. Revenue will also be acquired
through sponsors and from successful investigator driven study grants. Research has
demonstrated that industry pays for ~70% of clinical study costs in Australia
(Bourgeois, 2009) and hence it has been assumed that revenue raised from industry
invoicing for network services will equate to ~70% of the network costs. Investigators
will be charged for the services of the Network on a cost recovery basis too but some
services may be subsidised depending on the level of government infrastructure
funding. There will be certain infrastructure costs that cannot be allocated easily on a
project cost recovery basis. These positions require on-going government
infrastructure support. Alternatively, a levy could be charged to all endorsed studies to
cover these fixed infrastructure costs. Experience overseas is that paediatric study
networks can never be entirely funded on a cost recovery model from sponsored
studies. The model we have used will rely to some extent on ongoing government
funding after 5 years. Additional funds will also be sought from philanthropic sources.
Overall, the network will require ~$1.6M increasing to ~$1.8M over 5 years from
Australian Federal and State Governments. This amount is predicted to be
leveraged 2.3 fold in the first year and over 4.6 fold by year 5. This additional
commitment will allow the government’s current investment into clinical study
infrastructure to be maximised. For example, any NHMRC funded clinical studies will
have a much greater chance of success when endorsed and supported by the network.
Individual state investments into infrastructure (such as Melbourne’s Clinical Research
Development Office and Australian Paediatric Pharmacological Research Unit and
Sydney’s The Australian Children’s Clinical Trials Centre) will enjoy greater leverage
with a national network. The value added to the Australian economy will be also be
significant. In 2008 Nucleus Network was winner of the Governor of Victoria Export
Awards in the category of Emerging Exporter and winner of the Victorian Export Award
for Innovation Excellence. This demonstrated that clinical study management entities
can be successful business ventures and benefit the Australian economy, including the
export market. By far the most important value that this investment will deliver is the
increase in health benefits for children. It is estimated that for every $1 that is invested
in clinical research, there is a $2.10 benefit to the health of the nation (Access
Economics, 2003). This network will allow Australian children to access the most
promising treatments sooner and locally, for many families this benefit is priceless.
15
Key Milestones for Establishment of the Network:
•
•
•
•
•
•
•
•
•
Further consultation and generation of detailed plan including costing
Establish advisory committee
Tender for core coordinating centre host institution/s
Hire key staff for core coordinating centre
Write SOPs
Tender and establish Local Study Support Units
Provide training
Advertising the existence of the network, linking with industry, clinician and
other groups
Establish Clinical Expert Groups
Key Performance Indicators for the Network:
•
•
•
•
•
•
•
Number of industry studies
Number of investigator driven studies
Time to start-up
Recruitment rates
Recruitment success
Number of trained staff
Return on investment
7. REFERENCES
Access Economics, Exceptional Returns: The Value of Investing in R&D in Australia, A Report
commissioned by The Australian Medical Research Association, 2003
Australian Bureau of Statistics
http://www.abs.gov.au/Ausstats/[email protected]/mf/3201.0.
Bourgeois C, Inaugural Survey of Investigator Perceptions on the Value of Industry Funded
Clinical Research, a survey commissioned and presented by NSW Clinical Trials Business
Development Unit, 2009
FDA, Federal Register / Vol. 63, No. 231 / 1998 / Rules and Regulations, USA
Greener, M Bitter medicine. New regulations aim to address the dearth of clinical safety trials for
drugs used in children EMBO reports 2008 9 (6): 505–508.
Holt PG, Sly PD, Martinez FD, Weiss ST, Björkstén B, von Mutius E, Wahn U, Drug
development strategies for asthma: in search of a new paradigm. Nature Imm. 2004 Jul;
5(7):695-8
NHMRC funding statistics
http://www.nhmrc.gov.au/_files_nhmrc/file/grants/dataset/clinical_trials.xls
Paediatric Medicines Industry Scoping Study Final Report (May2009)
http://www.health.gov.au/internet/main/publishing.nsf/Content/8B74126C37F69636CA2575E00
0199B49/$File/Final%20Project%20Report%20May%202009.pdf
Pharmaceutical industry strategy group final report (Dec 2008)
http://www.innovation.gov.au/Industry/Pharmaceuticals/Documents/PISG_Final_Report.pdf
Tan E, Dosing information for paediatric patients: are they really “therapeutic orphans”?, Med.
J. Aust. 2003 Aug 18; 179(4):195-198.
16
8. APPENDICES
Appendix 1 - SWOT Analysis of the Australian Context for Paediatric Clinical
Research Studies
Strengths:
Population:
1. Many states are served by specialised paediatric hospitals, so the
participant population is often centralised
2. Australia has an ethnically diverse population
3. Australia is a market for paediatric drugs, so many commercially
sponsored trials conducted in Australia will be relevant to the sponsor
company’s customers
4. A network based in the southern hemisphere can allow companies with
"seasonal" drugs to continue research year round.
Resources:
5. Australia maintains high standards of paediatric medical education and
world class paediatric hospitals
6. Australian paediatric clinicians possess high research-literacy
7. Many Australian paediatricians have a track record in running sponsored
and investigator initiated clinical trials of a range of phases
8. The paediatric community in Australia has an excellent collegiate and
collaborative track record
9. There is a growing pool of trained paediatric research support staff
(research nurses, study coordinators, research assistants)
10. There are several Human Research Ethics Committees with expertise in
paediatric study review
11. There are good governance arrangements for paediatric research sites
12. Australian Standards of conduct and policies meet and exceed
international guidelines for good clinical research practice (GCP)
13. Standardised training options on GCP are available across states,
including tertiary courses and courses internal to institutions
14. A range of dedicated paediatric facilities are available for use in
research, such as Magnetic Resonance Imaging (MRI) scanners,
pathology facilities, rooms and beds for clinical research visits
15. Dedicated clinical trials staff are available in paediatric hospital
pharmacies.
16. Australia has capacity to host both early and late phase clinical trials for
a compound
17. Paediatric hospitals are collocated with universities and research
institutes, allowing for strong associations with research enabling
personnel and translational research opportunities
18. Paediatric specific research expertise exists and is being developed,
such as statisticians, clinical pharmacologists and data managers
dedicated to paediatric studies
Regulatory approvals:
19. Gaining regulatory approval to conduct clinical trials is rapid, via a
notification to the Australian Therapeutic Goods Administration (TGA)
17
Weaknesses:
Population
1. Small patient numbers at each site limit the potential for single-site trials,
especially for rare diseases
2. Comprehensive data on participant populations nationally is unavailable
3. Poor patient referral networks inhibit recruitment
Logistics
4. Great distances between states affects ease of multi-site study
coordination
5. Ethical review and approval for multiple sites is inefficient and delayprone
Research Infrastructure
6. A deficient infrastructure and investigator base for paediatric studies
affects industry because it means that multicentre paediatric trials
cannot be easily implemented. Factors currently inhibiting multicentre
investigator initiated paediatric trial activity, and therefore capacity for
industry trials, are outlined in points 7-18 below.
The following factors currently inhibit Paediatric research capacity:
7. Even in ‘research hubs’ (universities, hospitals and medical research
institutions) there are no organisations for whom clinical research is
‘core business’
8. Natural collaboration between investigators in each paediatric specialty
is sometimes hindered by the distance between their institutions
9. The lack of facilitation and formality of collaborations across hospitals
means they can be awkward to establish and work within
10. Much inefficiency and duplication of effort results from research staff
operating in ‘silos’ within departments, often isolated from other
researchers and/or support
11. Many investigators do not have ready access to expert research
enablers, such as biostatisticians and clinical pharmacologists. This
type of expertise is currently unevenly distributed between different sites
and states.
12. Even where these enablers are accessible, individual investigators’
awareness, understanding and use of enablers can be limited
13. The lack of a support structure for clinicians wishing to do clinical
research, means many potential investigators are not developed to their
potential and many important research questions remain unanswered
14. Clinical trials conduct and data management is intensive – but there is
no shared infrastructure (such as software) to ease this and it has not
been feasible for this to be arranged by individuals.
15. Many investigators’ time is taken up by tasks that could be delegated to
support staff, but staff recruiting (especially for part-time roles) is difficult
at the individual level
16. As research personnel are employed for certain projects (rather than for
core positions), research skills and capacity are lost when projects finish
17. Clinical research is expensive and studies can be lengthy. This creates
inequalities in competition for grant funding
18. Arranging for staff that work across departments and studies, let alone
institutions, such as recruitment officers, is near impossible due to
funding arrangements.
19. Currently there are no consistent national standards for paediatric
clinical trials.
18
Opportunities:
1. The current government focus on clinical trials in Australia represents an
opportunity for action
2. Collaborative and cooperative links are forming between groups who
share the goal of enhancing clinical research capacity in Australian
Paediatrics
3. Paediatric health care and research institutions are increasingly
recognising the importance of being engaged in clinical research
4. Wide support for a paediatric research network exists across the country
5. Some groups currently have part funding to support the development of
initiatives such as the proposed Network (for example, the Clinical
Research Development Office in Melbourne)
6. Substantial expertise is available in Australia and could be shared for
maximum benefit
7. There are several recently funded paediatric research collaborations (for
example CCREs) that
require enabling through the type of
infrastructure to be developed in the proposed Network
8. Child health is increasingly on the global political agenda
9. Australia can learn from the experience of UK, The Netherlands and
USA and further liaise with these groups to achieve best-practice in the
operation of an Australian network
10. FDA/EMEA incentives are increasing the number of paediatric trials that
could potentially be conducted in Australia.
11. To attract investment in trials, Australia must develop specialised
capacity, rather than a ‘race to the bottom’ over lowest pricing.
Paediatric research capacity is an example of such an option.
Threats:
1. Often hospital based research facilities are vulnerable to funding
fluctuations of health care budgets; this is a threat to the sustainability of
clinical trial infrastructure at some sites.
2. Understanding of the role and importance of research can be low within
some Hospital administrations.
3. International competition for industry sponsored paediatric trials, including
countries better positioned to offer lower costs
19
Appendix 2 - Support for the proposed Treatments for Children Research
Network
The following people have contributed to this proposal and are prepared to be involved
in the proposed Network and/or support its development (alphabetical order).
Adelaide
Dr Helen Marshall
Senior Medical Practitioner, Department of Paediatrics, Women’s and
Children’s Hospital
Director, Vaccinology and Immunology Research Trials Unit (VIRTU),
Discipline of Paediatrics, Women’s and Children’s Hospital
Senior Lecturer, Discipline of Paediatrics, School of Paediatrics and
Reproductive Health, University of Adelaide
Senior Lecturer, Discipline of Public Health, School of Population
Health and Clinical Practice, University of Adelaide
Brisbane
Dr Andrew Cotterill
Dr Anne Chang
Professor Keith
Grimwood
Associate Professor
Michael Nissen
Professor Peter Sly
Dr Claire
Wainwright
Director, Paediatric Endocrinology and Diabetes, Mater Children’s
Hospital, Brisbane
Paediatric Respiratory and Sleep Physician
NHMRC Practitioner Fellow
Professorial Fellow, Menzies School of Health Research, Darwin
Honorary Professor, University of Sydney
Dept of Respiratory Medicine
Royal Children's Hospital, Brisbane
Director, Queensland Children’s Medical Research Institute
Director, Queensland Paediatric Infectious Diseases Clinical Trials
Centre
Director, Infectious Diseases & Clinical Microbiologist, Royal Children's
Hospital, Brisbane & Pathology Qld
Associate Professor in Infectious Diseases, Microbiology & Paediatrics,
Griffith University & University of Qld
Respiratory Physician, Royal Children’s Hospital, Brisbane
Senior Clinical Research Fellow, Queensland Children's Medical
Research Institute.
Professor, University of Queensland
Director, WHO Collaborating Centre for Research on Children's
Environmental Health.
Adjunct Professor, School of Paediatrics and Child Health,
University of Western Australia
Adjunct Professor, School of Public Health, Curtin University of
Technology.
Respiratory Physician and Head of Cystic Fibrosis Services, Royal
Children’s Hospital, Brisbane
Associate Professor, Department Paediatrics and Child Health,
University of Queensland and Queensland Children’s Medical
Research Institute
Darwin
Associate Professor
Ross Andrews
Associate Professor
Peter Morris
Leader, the Child Health Division, Menzies School of Health Research,
Darwin
Deputy Leader, the Child Health Division, Menzies School of Health
Research, Darwin
Associate Professor of Paediatrics, Northern Territory Clinical School,
Flinders University & Royal Darwin Hospital
20
Melbourne
Associate Professor
David Ashley
Associate Professor
Franz Babl
Professor Julie
Bines
Professor John
Carlin
Associate Professor
Noel Cranswick
Associate Professor
Andrew Davidson
Professor Terry
Dwyer
Professor Paul
Monagle
Professor Terry
Nolan
Professor Mike
South
Ms Emma Watts
Director Children’s Cancer Centre
Royal Children’s Hospital
Murdoch Children’s Research Institute
CEO Australian Children’s Cancer Trials (ACCT)
Director Paediatric Integrated Cancer Service
Group leader, emergency research, Murdoch Children's Research
Institute, Royal Children's Hospital, and University of Melbourne
Victor and Loti Smorgon Professor of Paediatrics,
The University of Melbourne
Head, Intestinal Failure and Clinical Nutrition Research Group,
Leader, RV3 Rotavirus Vaccine Program,
Murdoch Children’s Research Institute
Head, Clinical Nutrition Program and Gastroenterologist,
Royal Children’s Hospital, Melbourne
Head, Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s
Research Institute & University of Melbourne Department of Paediatrics
Professorial Fellow, Centre for Molecular, Environmental, Genetic &
Analytic Epidemiology, School of Population Health, University of
Melbourne
Head, Australian Paediatric Pharmacology Research Unit
Royal Children’s Hospital, Melbourne
Murdoch Children’s Research Institute
Head, Clinical Research Development Office
Murdoch Children’s Research Institute
Paediatric Anaesthetist and Trialist
Royal Children’s Hospital, Melbourne
Director, Murdoch Children’s Research Institute
Stevenson Professor & Head of Department
Department of Paediatrics, The University of Melbourne
Paediatric Haematologist, Head of Haematology Department
Royal Children's Hospital, Melbourne
Honorary Fellow, Critical Care and Neurosciences
Murdoch Children’s Research Institute, Melbourne
Head, Vaccine and Immunisation Research Group and Director of the
NHMRC CCRE on Child and Adolescent Immunisation
Head, Melbourne School of Population Health, The University of
Melbourne
Professorial Research Fellow, Murdoch Children's Research Institute
Paediatrician & Intensivist,
Director, Department of General Medicine, Royal Children’s Hospital
Research Fellow, Murdoch Children's Research Institute
Professor of Paediatric Medicine, University of Melbourne
Clinical Research Development Officer,
Murdoch Children’s Research Institute
Research Governance Officer, Royal Children’s Hospital, Melbourne
Perth
Dr Peter Richmond
Director, Child Health Research Network, Children and Adolescent
Health Service
Director, Vaccine Trials Group, Consultant Paediatric Immunologist and
Paediatrician,
University of WA School of Paediatrics and Child health
Telethon Institute for Child health research
Princess Margaret Hospital for Children
21
Professor Stephen
Stick
Head, Department of Respiratory Medicine
NHMRC Practitioner Fellow
Princess Margaret Hospital for Children
School of Paediatrics and Child Health
University of Western Australia
Sydney
Professor Ian
Alexander
Professor Nadia
Badawi
Professor Louise
Baur
Professor Robert
Booy
Associate Professor
Joshua Burns
Dr Patrina Caldwell
Associate Professor
Chris Cowell
Dr Jeffrey Chaitow
Professor Jonathan
Craig
Professor Mark
Dadds
Dr Jonathan Egan
Dr Marino Festa
Dr Madlen Gazarian,
Associate Professor
Adam Jaffe
Dr Kimberley
Lilischkis
Professor Glenn
Marshal
Professor in Paediatrics & Molecular Medicine, Paediatrics & Child
Health, The University of Sydney
Senior Staff Specialist at The Children’s Hospital at Westmead Head,
Gene Therapy Research Unit, Kids Research Institute at The
Children’s Hospital at Westmead.
Clinical Associate Professor, Paediatrics & Child Health, The University
of Sydney
Head, Neonatology Department, The Children’s Hospital at Westmead.
Director of Weight Management Services, The Children’s Hospital at
Westmead;
Professor, Discipline of Paediatrics and Child Health, University of
Sydney
Director, Child & Adolescent Obesity Clinics Of Australasia Network
(CAOCOA-Net)
Director, National Centre for Immunisation Research and Surveillance
Professor, Paediatrics & Child Health, The University of Sydney
Podiatrist and Head of Clinical Research, Institute for Neuroscience
and Muscle Research, The Children’s Hospital at Westmead
Senior Lecturer, Paediatrics & Child Health, The University of Sydney
Staff Specialist, Department of Nephrology, The Children’s Hospital at
Westmead
Acting Director, Kids Research Institute at The Children’s Hospital at
Westmead.
Paediatric Rheumatologist, The Children’s Hospital at Westmead.
Professor Clinical Epidemiology, Public Health, School of Public
Health, The University of Sydney
Head, Centre for Kidney Research, Kids Research Institute at The
Children’s Hospital at Westmead.
Professor, School of Psychology, University of New South Wales
National Health & Medical Research Councils Senior Research Fellow
Staff Specialist, PICU, The Children’s Hospital at Westmead
Senior Lecturer, Paediatrics & Child Health, the University of Sydney
Staff Specialist, Intensive Care Department, The Children's Hospital at
Westmead
Head, Paediatric Therapeutics Program
Senior Lecturer, School of Women's and Children's Health , University
of New South Wales
Paediatric Clinical Pharmacologist and Rheumatologist ,Sydney
Children's Hospital
Consultant in Respiratory Medicine
Head of Respiratory Department
Sydney Children's Hospital and Conjoint Appointee
School of Women's and Children's Health, University of NSW
Project Coordinator, Australian Children’s Clinical Trials Centre, Kids
Research Institute at The Children’s Hospital at Westmead.
Paediatric Haematologist and Oncologist,
Professor of Paediatrics
Director, Centre for Children's Cancer and Blood Disorders, Sydney
Children's Hospital, Head, Molecular Carcinogenesis Program,
Children’s Cancer Institute Australia.
22
Dr Mary McCaskill
Professor Peter
McIntyre
Professor Kathy
North
Associate Professor
Andrew Rosenberg
Mrs Susan Smith
Dr Hiran Selvadurai
Professor Peter van
Asperen
Dr Charles Verge
Associate Professor
Katrina Williams
Dr Nick Wood
Associate Professor
John Ziegler
Co-Chair, Department of Accident and Emergency, The Children’s
Hospital at Westmead
Director, National Centre for Immunisation Research and Surveillance
Professor, Paediatrics & Child Health, Children's Hospital, Westmead
Paediatric Neurogeneticist, Associate Dean and Head, Discipline of
Paediatrics and Child Health, The University of Sydney
Head, Institute for Neuroscience and Muscle Research, The Children's
Hospital at Westmead
Head, Department of Nephrology
Sydney Children's Hospital
Associate Professor, School of Women's and Children's Health,
University of NSW
Trials Co-ordinator, Sydney Children's Clinical Trials Centre
Clinical Senior Lecturer, Paediatrics & Child Health, The University of
Sydney
Staff Specialist, Department of Respiratory Medicine,
The Children's Hospital at Westmead
Macintosh Professor of Paediatric Respiratory Medicine,
University of Sydney,
Head, Department of Respiratory Medicine,
The Children's Hospital at Westmead
Paediatric Endocrinologist, Sydney Children's Hospital
Senior Lecturer, School of Women's and Children's Health, University
of NSW
Community Paediatrician, Sydney Children's Hospital
Co-ordinator of Clinical Research, Sydney Children's Hospital,
Associate Professor, School of Women's and Children's Health,
University of NSW
Staff Specialist, General Medicine, The Children’s Hospital at
Westmead
Head, Department of Immunology and Infectious Diseases Sydney
Children's Hospital , Associate Professor, School of Women's and
Children's Health, University of NSW
Support from existing Australian paediatric research groups
The following groups have been consulted on the concept of the Network and have
stated their intent to be involved:
• PREDICT network (emergency medicine)
• Australian Children’s Cancer Trials (ACCT)
• The Australasian Paediatric Respiratory Group
• The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST
CF)
• Australian Paediatric Rheumatology Group (APRG)
• Paediatric SIG of the Thoracic Society of Australia and New Zealand (TSANZ)
• Australasian Paediatric Endocrine Group
• Australian and New Zealand Paediatric Nephrology Association (ANZPNA)
• The Child & Adolescent Obesity Clinics Of Australasia Network (CAOCOA-Net)
• National Vaccine Research Network (A collaborating group without formal
governance)
• Paediatric Study Group at Australian and New Zealand Intensive Care Society
(ANZICS)
• Indigenous Trials Network (Currently a planned initiative, lead by Menzies School
of Health Research & NHMRC Clinical Trials Centre)
23
State versus nationwide networks
Support for a paediatric trial network has recently been demonstrated in NSW. In
December 2008 the NSW Office of Science and Medical Research (OSMR) hosted a
Paediatric Research Roundtable that was attended by all three major paediatric tertiary
treatment centres and neonatal care units in NSW. There was unanimous support for a
paediatric research network to be formed in NSW to facilitate high quality clinical trials
into medicines and other therapeutic interventions for children and adolescents. OSMR
agreed to convene a working group to consider and deliver the next steps for the NSW
“Better Treatments 4 Kids” network.
Key supporters of this proposal for a National Treatments for Children Research
Network were also involved in the NSW roundtable discussions. The proposed
National Network has recognised major advantages over any state specific approach,
primarily greater capacity for trials through access to a larger network of investigators
and larger pools of participants and most efficient use of resources within a single
structure. Other advantages of a National network include reduction of duplication of
effort, avoidance of counterproductive inconsistencies and rivalries across states,
encouragement of wider collaborations and a sense of shared ownership.
The authors of this proposal are aware of other clinical trial collaborations and leading
clinical investigators for whom the network could be of value, and will continue to
consult widely with the aim of maximising the national scope and relevance of the
proposal.
24
Appendix 3 –
Proposed Network process and functions for investigator-initiated proposals.
Figure 6 – Representation of proposed flow of network study development
a. CONCEPT PROPOSALS
A Proposing Investigator is any person or group who develops and submits a proposal
for a study to the Network’s Coordinating Centre. Proposal submission is open to all,
although it is expected that the majority of proposals will originate from paediatric
clinician researchers and from the Network’s Clinical Expert Groups (CEGs). The
Network Coordinating Centre will arrange proposal development workshops
periodically for interested parties.
Generally, the Proposing Investigator, or a representative of the proposing group, will
become the Chief Investigator of the trial if it is conducted.
Concept Proposals will be accepted by the Network Coordinating Centre on a
standardised template of 2 pages. Complete Concept Proposals will be forwarded to
the appropriate Clinical Expert Group (CEG) for consideration and their
recommendations will be communicated to the Proposing Investigator.
b. NETWORK INVOLVEMENT DETERMINED
Once a CEG deems a proposal acceptable, the level of possible support for the
development and management of the project is determined at the Coordinating Centre
prior to adoption into the Network’s portfolio of studies. For example, involvement may
or may not include: full protocol development, central data management, central study
management, secondment of network’s study nurses. Factors determining level of
involvement include: requirements of study, likely funding, Proposing Investigator’s
wish and the Network’s portfolio development strategy. A brief written work plan will be
produced from a standardised template as the level of involvement is decided.
25
c. PROTOCOL MANAGEMENT TEAM FORMED
Funding Application
Proposals adopted into the Network’s portfolio will be assigned a small team to create
an application for funding, such as an NHMRC grant application. Figure 7indicates the
team’s composition at this funding application stage and subsequent stages. Projects
costs will be calculated using a standard template, including time fractions of Network
staff that will work on the study following the acquisition of funding. The costs of
Network staff time used for producing funding applications will not be recovered, but
will be paid from core funding.
Figure 7 Protocol Management Team composition and involvement over time
Funding
Application
Protocol
Development
Trial Set-up
Trial Conduct
Dissemination
Biostatistician
Formulations
chemist
Other Advisory*
Grants Officer
Trial Manager
Information
Systems
Data
Management
Proposing
Investigator**
Key – Approximate weekly time-commitment (per trial)
High
Moderate
Low
None
*Other advisory would be clinical pharmacologist, health economist, pathology advisor,
consumer representative, as required
** All members, besides the proposing investigator/s, will be Network staff
Protocol Development
Only studies with adequate funding (or acceptable funding plan) will progress to the
protocol development stage. The team assigned to the project will generally have
strong continuity of membership from the funding proposal team, and the members will
collaboratively write the full trial protocol.
Trial Set-up and Conduct
The team meet at least every six weeks during the set-up and conduct of the trial. The
role of Information Systems Personnel is to develop the electronic or paper CRF for the
trial and the associated database. Data management for each trial will be centralised at
26
the coordinating centre, employing a Trial Data Management System. A Trial Manager
will be assigned to each trial to coordinate the multiple investigator teams across sites.
They will remotely oversee ethics submissions, protocol compliance, participant
recruitment, data collection and maintenance of study documents at every site
participating in the trial. If deemed necessary, the Network’s Local Study Support Units
(LSSUs) may be engaged in investigator-initiated trials, such as by providing
investigator support staff to participating investigators, or by enhancing recruitment via
dedicated local recruitment officers.
Dissemination
Relevant members of the protocol development team will prepare manuscripts for
journal articles and submit them for publishing, following the analysis of results. The
Network will promote publishing and authorship guidelines in line with the Australian
Code for the Responsible Conduct of Research. Involvement of the Network should be
acknowledged in all presentations of results.
The network will ensure access to Knowledge Translation experts and communication
of results to the public will form part of the Networks coordinated consumer liaison
activities.
27
Appendix 4 How the Network’s Services will enhance industry sponsored trials
1. The Network will enhance the speed of start-up for industry sponsored trials
A single access point is convenient and efficient
•
•
A single point for guided access to paediatric investigators and research
infrastructure across Australia will be offered by the Network.
Dedicated industry liaison staff will ensure a rapid response to enquiries and
requests.
Feasibility assessments and adoption processes will be prompt and reliable
•
•
•
•
•
Basic feasibility assessments (judging a trial’s suitability for Australia) will be
conducted in under 10 days via members of relevant ‘Clinical Expert Groups’
coordinated by the Network.
Complete feasibility assessments will be conducted by collecting responses
from potential participating paediatric investigators across Australia, and using
information from a database of patient numbers, available facilities,
investigators and past recruitment rates. Feasibility assessments will be
completed in under 4 weeks following receipt of the request by the Network,
following confidentiality agreements.
A decision regarding the suitability (according to capacity and strategy) of the
Study for adoption into the Network’s portfolio will be made rapidly at the
completion of the feasibility assessment.
A standardised costing template will be used for all studies, to enable more
efficient budget negotiation.
Completion of standard agreements for network involvement, site involvement
and the use of other facilities will be coordinated by the Network.
Scientific, ethics and governance approvals will be triaged
•
•
•
•
In establishing the network, the participating sites will have impetus to
implement the HoMER (Harmonisation of multicentre ethical review) approach
for streamlined ethical review and additional streamlining measures, including
adopting a single paediatric consent form template and harmonised governance
procedures.
Ethics Submissions will be conducted by dedicated staff to maximise efficiency.
Governance Submissions will be conducted by dedicated staff, familiar with
local requirements, to maximise efficiency.
Network staff will undertake the administrative work of investigators’ ethics and
governance reporting responsibilities, to maximise productivity.
28
2. The Network will enhance recruitment into industry sponsored trials:
Recruitment efforts will be actively enhanced
•
•
•
•
•
•
The network will provide single-point access to several sites serving a
considerably larger population than is accessible in any single region.
Dedicated recruitment officers will be available across the network, to facilitate
recruitment efforts, such as advertising to potential participants and education
of treating clinicians about each trial to secure their cooperation.
Recruitment officers may implement recruitment rescue strategies when
required (as determined by the sponsor company). This may include, examining
the reasons for poor adoption that may be remedied (such as subsidised
parking or meal vouchers for families) and re-examining the protocol with
consumer groups to see if it can be made less arduous
Recruitment rates will be monitored across all studies.
With the availability of network support, junior Investigators can be supported
and trained in conducting network-adopted studies, and contribute to strong
recruitment.
Properly conducted feasibility assessments will also contribute realistic
recruitment estimates and well guided site selection, before study
commencement.
Patient referral networks will increase participation in trials
•
•
•
•
•
A public website of all ongoing studies with participants under 18 years old,
grouped by indication, will be available for interested families and health care
providers, and will provide information enabling self-referral to appropriate trial
teams.
The network’s consumer liaison officer will engage in coordinated association
with community groups, general practitioners and other healthcare providers,
and encourage increased participation in clinical studies.
The nation-wide operation of the Network, and locally visible Study Support
Units, will raise awareness of clinical trials amongst clinicians, increasing the
culture of involving their patients in clinical trials.
The network’s consumer liaison activities will also be focused on raising
awareness of clinical trials amongst children and the general community,
including educational material accessible on the public website.
Investigators and potential participants will be attracted by the Networkbranding of successively adopted studies, once the network has become
established.
29
3. The Network will enhance quality for industry sponsored trials:
Skills and expertise
•
•
•
•
•
•
Sponsors will have access to the network’s expertise for advice on formulations,
paediatric ethical matters, consumer views and other issues particular to each
trial
Consumer input, available through the network coordinating centre, can ensure
studies are relevant and appropriate for children and their families
Skilled paediatric research staff will be engaged in network studies, as the
volume of network studies will create sustainable roles, working relationships
and training opportunities
Minimum training standards will apply to personnel working on network studies
and standardised training will be provided across all states
A quality workforce will be further assured through network assisted recruitment
of investigator support staff, and the availability of experienced staff for
secondment to investigators’ teams
The network will support collegiality amongst investigator support staff in each
region, through forums such as a web portal and annual event
Network management and oversight
•
•
•
•
•
The network structure, with a core coordinating centre and local study support
units in each region, offers an efficient national approach to clinical trials.
The network core coordinating centre will oversee the national activity of the
network and manage the performance of the Local Study Support Units, as well
as managing resource allocation appropriately
The activity of the network will be a standardised by a comprehensive set of
SOPs, ensuring consistent best practice at network study sites through both
study set up and conduct.
A database will be maintained at the Network coordinating centre, tracking
relevant performance metrics for all network adopted paediatric trials
Invoices and payments will be generated and tracked from a single point, for
simplicity
30
Appendix 5 - Five Year Financial Projections for “Treatments for Children Research Network – Australia”
Model 1.1
The 2010 base year reports the TCRN operating with minimal FTEs that can be increased in line with activity.
Goods & Services, Repairs & Maint. and Revenue ERE (FTE Increases) Activity
40% 54% 72% 84% 98% 100% Director 1 1 1 1 1 1 Industry Liaison Officer CEGs Administrative Coordinator Clinical pharmacologist Formulations Chemist Consumer Liaison Officer Administrative Support Business Dev. Manager Network Dev. Officer Statisticians Health economist Information Systems Dev. Study Managers Data Managers Grants Writing Officer Study Admin. Coord.(LSSU) Recruitment Officer (LSSU) Study Coordinator (LSSU) 1 1 1.5 1.5 2 2 1 0.2 0.2 0.5 1 0.4 2 1 0.2 1 1 0 1 4 4 4 1 0.4 0.6 0.6 1 0.5 2 2 0.4 1 4 0.5 1 5 5 5 1 0.6 1 0.6 1.4 0.6 2.5 2.5 0.5 1 8 1 1.5 6 6 6 1 0.8 1.2 0.8 1.6 0.8 2.5 2.5 0.6 1 10 1.5 1.5 7 7 7 1 1 1.5 1 1.8 1 3 3 0.8 1 12 2 2 8 8 8 1 1 2 1 2 1 3 3 1 1 12 2 2 8 8 8 23.5 32 42.7 49.3 58.1 59 TOTAL FTE 31
Sum of Amount Category 1 Category 2 2010/11 Account Description BASE YR 2011/12 2012/13 ANL YR 1 ANL YR 2 1. REV 1. REV Federal Government Support 1,071,225 State Government Support 642,735 Competitive Project Funding 650,000 Industry Funding for Services 3,439,375 Philanthropic Funding 53,561 1. REV Total 3,712,466 1. REV Total 3,712,466 4,621,335 5,856,896 4,621,335 5,856,896 Director 187,000 1,147,523 1,187,686 665,231 688,514 712,612 870,000 1,100,000 1,200,000 4,142,658 5,014,944 5,279,655 55,436 57,376 59,384 6,842,043 8,008,357 8,439,338 6,842,043 8,008,357 8,439,338 210,350 218,764 227,514 143,420 198,876 206,831 78,740 81,890 85,166 168,280 218,764 227,514 113,386 147,402 204,398 62,992 81,890 85,166 86,390 101,076 116,799 76,491 99,438 103,415 2. ERE 1,108,718 2. ERE ANL YR 5 51,750 50,000 ANL YR 4 2,513,585 1,862,466 ANL YR 3 400,000 200,000 2015/2016 621,000 600,000 2014/2015 1,035,000 1,000,000 2013/14 194,480 202,259 Industry Liaison Officer 85000 88,400 137,904 CEGs Admin. Coordinator 70000 72,800 75,712 Clinical pharmacologist 37400 77,792 121,356 Formulations Chemist 16800 52,416 90,854 Consumer Liaison Officer 35000 43,680 45,427 Administrative Support 48000 49,920 72,684 Business Dev. Manager 34000 44,200 55,162 32
Network Dev. Officer 170000 176,800 229,840 239,034 298,314 310,246 239,034 298,314 310,246 57,368 79,550 103,415 86,615 90,079 93,682 787,405 982,681 1,021,988 67,492 93,589 97,332 118,111 163,780 170,331 551,183 655,121 681,326 551,183 655,121 681,326 551,183 655,121 681,326 4,188,656 5,119,769 5,408,022 11,630 14,185 14,909 11,630 14,185 14,909 4,652 5,674 5,964 4,652 5,674 5,964 116,297 141,853 149,093 116,297 141,853 149,093 Statisticians 85000 176,800 229,840 Health economist 17000 35,360 45,968 Information Systems Dev. 77000 80,080 83,283 Study Managers 70000 291,200 605,696 Data Managers 0 20,800 43,264 Grants Writing Officer 70000 72,800 113,568 Study Admin. Coordinator 280000 364,000 454,272 Recruitment Officer 280000 364,000 454,272 Study Coordinator 2. ERE Total 3. G&S 3.1 Food Special Functions Food 3.1 Food Total 3.4 Special Services 280000 364,000 1,842,200 2,569,528 5,000 7,047 5,000 7,047 454,272 3,515,633 9,732 9,732 Spec Services Other 2,819 2,000 3,893 3.4 Special Services Total 3.6 Administration Advertising Recruitment Conference Fees, Domestic Travel, Other 2,000 2,819 3,893 70,468 97,322 50,000 50,000 70,468 97,322 33
Courier & Freight 7,047 5,000 9,732 Data Records & Storage 7,047 5,000 9,732 Functions 97,322 Information & Communication 20,000 Info Man Software Licences 10,000 28,187 38,929 14,094 19,464 Legal Other 9,732 Postal 9,732 Print & Stat Other 9,732 CEG expenses 23,357 Stationery 9,732 3.6 Administration Total
222,000 229,000 312,878 432,109 322,744 445,734 4. RMR New Computer Equip Computer Software Licence & Admin Replacement Computers Replacement Comp Software Licence + Admin 47,000 17,595 22,924 Database and annual fee 23,500 8,798 11,075 ‐ ‐ ‐ 35,000 23,259 28,371 29,819 11,630 14,185 14,909 11,630 14,185 14,909 11,630 14,185 14,909 27,911 34,045 35,782 11,630 14,185 14,909 516,361 629,829 661,971 532,642 649,688 682,844 14,635 20,196 2,138 6,831 9,108 931 52,110 20,191 27,227 26,055 9,754 12,278 5,356 5,544 5,738 104,987 64,793 48,312 4. RMR Total 59,637 56,741 4. RMR 46,519 3. G&S Total
149,093 7,047 5,000 141,853 16,912 12,000 116,297 7,047 5,000 14,909 7,047 5,000 14,185 7,047 5,000 11,630 14,909 14,185 70,468 50,000 11,630 5,000 31,393 5,175 34
105,500 39,174 ERE Overheads (25% for CHW) 460,550 642,382 878,908 1,047,164 1,279,942 1,352,006 44,634 50,014 51,181 5,918,083 7,164,206 7,542,365 Grand Total (Revenue ‐ Expenditure) 1,051,801 1,030,499 943,503 923,960 844,151 Assumptions
3.5% CPI 4.0% Employee Award Increases year on year (Inline with the NSW Department of Health award increases) 25.0% Overheads ‐ Employee Related (Inline with CHW) 7.0% Overheads ‐ Goods and Services + Repairs and Maintenance (Inline with CHW) These staff positions will only be filled upon demand and will be subsidised by industry clinical trial funding These staff positions will only be filled upon demand and will be subsidised by grant funding for investigator‐driven studies These staff positions could be subsidised from industry and grant funding on a cost recovery basis NSW Health Awards Rates have been used for estimating the salary levels NSW Health Award
Level
Rate
187000 Staff Specialist Senior 85000 Health Service Manager Level 2 70000
Health Service Manager Level 1 84000 Health Professional (Chemist) Grade 3 48000 Admin. Officer Level 3 896,973 G&S and RMR Overheads (7% for CHW) 23,415 Total Expenditure (including overheads) 2,660,665 24,790 33,944 3,590,836 4,913,393 Computer Staff Programming Supervisor Computer Staff Data Input 77000 40000 35