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Department of Health

Review of the Australian NewZealand Clinical Trials Registry

Final Report

August 2018

212 Clarendon Street | East Melbourne | Victoria | 3002 | +61 (0) 3 9419 0006aspexconsulting.com.au

Department of HealthReview of ANZCTR

Final reportAugust 2018

TABLE OF CONTENTS

List of Abbreviations........................................................................................................

1 Executive Summary.........................................................................................................

1.1 Current role and purpose...................................................................................

1.2 Literature review and jurisdictional scan............................................................

1.3 Performance assessment..................................................................................

1.4 Strategic responses & options...........................................................................

2 Context and purpose.......................................................................................................

2.1 Context...............................................................................................................

2.2 Purpose..............................................................................................................

3 Current arrangements......................................................................................................

3.1 Current role........................................................................................................

3.2 Key functions.....................................................................................................

3.3 Operational context............................................................................................

4 Findings from literature review and jurisdictional scan....................................................

4.1 Definitions..........................................................................................................

4.2 Role and purpose...............................................................................................

4.3 Policy and funding context.................................................................................

4.4 Current landscape..............................................................................................

4.5 Expectations on reporting and compliance........................................................

4.6 Other jurisdictional approaches..........................................................................

4.7 Forefront and future...........................................................................................

4.8 Summary............................................................................................................

5 Stakeholder themes.........................................................................................................

5.1 Scope of consultations.......................................................................................

5.2 Role....................................................................................................................

5.3 Functionality.......................................................................................................

5.4 Data Integrity......................................................................................................

5.5 Enhancements...................................................................................................

5.6 ClinicalTrials.gov................................................................................................

5.7 Other Innovations...............................................................................................



6 Strategic response...........................................................................................................

7 Implementation issues.....................................................................................................

Appendix 1 Stakeholder discussion guide................................................................

Appendix 2 List of stakeholders consulted................................................................

Appendix 3 Current IT Infrastructure.........................................................................

Appendix 4 Publications by the ANZCTR.................................................................

Index of Figures

Figure 1-1: Investment logic map........................................................................................

Figure 1-2: Summary of options..........................................................................................

Figure 1-3: Implementation timeframes by option...............................................................

Figure 2-1: Project methodology.........................................................................................

Figure 3-1: Process map of ANZCTR trial registration and update steps............................

Figure 3-2: User perceptions of the ANZCTR, 2009 to 2016-17.........................................

Figure 3-3: Trend in FTE by staff category, ANZCTR, 2013 to 2017..................................

Figure 4-1: Policy and funding map for ANZCTR................................................................

Figure 4-2: New frontier of transparency in clinical trial reporting systems.........................

Figure 6-1: Investment logic map........................................................................................

Figure 6-2: Summary of options..........................................................................................

Figure 7-1: Implementation timeframes by option...............................................................

Index of Tables

Table 3-1: List of data items required by the WHO............................................................

Table 3-2: Additional items for collection at time of registration.........................................

Table 3-3: Type of ANZCTR user, 2009 to 2016................................................................

Table 3-4: ANZCTR Advisory Committee membership......................................................

Table 3-5: Staffing profile for the ANZCTR, 2013 to 2017.................................................



Table 3-6: Relative share of FTE by staff category, ANZCTR, 2013 to 2017.....................

Table 3-7: FTE breakdown by core and one-off staff, ANZCTR, 2017...............................

Table 4-1: Key attributes of clinical trial registries..............................................................



List of AbbreviationsACNC Australian Charities and Not-for-Profit Commission

ACTA Australian Clinical Trial Alliance

ANZCTR Australian New Zealand Clinical Trials Registry

ANZGOG Australia New Zealand Gynaecological Oncology Group

API Application Programming Interface

ASP Active Server Pages

AU RED Australian Research Ethics Database

CPU Central Processing Unit

CTC Clinical Trials Centre

CTJWG Clinical Trials Jurisdictional Working Group

CTPRG Clinical Trials Project Reference Group

DIIS Department of Industry, Innovation and Science

ERM Ethics Review Manager

FDA Food and Drug Administration

FHIR Fast Healthcare Interoperability Resources

Gb Gigabyte

HREC Human Research Ethics Committee

ICMJE International Committee of Medical Journal Editors

ICTRP International Clinical Trials Platform

Mb Megabyte

MS SQL Microsoft Structured Query Language

NAS National Aggregate Statistics

NHMRC National Health and Medical Research Council

NIH National Institutes of Health

NMA National Mutual Acceptance



RAM Random Access Memory

REGIS Research Ethics and Governance Information System

RGMS Research Grants Management System

RGS Research Governance Systems

SEPTRE SPIRIT Electronic Protocol Tool & Resource

SOPs Standard Operating Procedures

SPIRIT Standard Protocol Items: Recommendations for Interventional Trials

Tb Terabyte

TIA Therapeutic Innovation Australia

TOGAF The Open Group Architectural Framework

UPS Uninterruptable Power Supply

UTN Universal Trial Number

WHO World Health Organisation

YTD Year to Date

Disclaimer

Please note that, in accordance with our Company’s policy, we are obliged to advise that neither the Company nor any employee nor sub-contractor undertakes responsibility in any way whatsoever to any person or organisation (other than the Australian Government Department of Health) in respect of information set out in this report, including any errors or omissions therein, arising through negligence or otherwise however caused.



1 Executive Summary

Aspex Consulting was engaged by the Australian Government Department of Health to undertake an independent review of the Australian New Zealand Clinical Trials Registry (ANZCTR). The review had three objectives: To identify best practice approaches for contemporary clinical trial registries through a literature

review and jurisdictional scan; To assess ANZCTR’s performance in terms of appropriateness, value for money, alignment to

stakeholder requirements and best practice; and To recommend practical options for improvement for a potential next generation clinical trial

registry.

The focus of the review was on the Registry’s role and function, it was not a review of the management or governance of the ANZCTR.

1.1 Current role and purpose As one of 15 WHO Primary Registries, ANZCTR’s core role is to make public all clinical trials that are being conducted in the region served by the registry, namely, Australia and New Zealand. Consistent with its WHO mandate, ANZCTR strives to achieve the following goals: Improve research transparency; Facilitate trial participation; Avoid duplication; Identify potential research areas; Promote research collaboration; and Improve trial quality.

1.2 Literature review and jurisdictional scanThere are future opportunities for enhancing the role of the registry, influenced by a continuing trend for strengthening the transparency of clinical research. Registries in other jurisdictions have already adopted the reporting of results as a core requirement of registration – this is yet to occur for the ANZCTR. The next boundary being pushed, again in the interest of research transparency, is the sharing of individual participant data. This stage has yet to be implemented internationally.

Within the Australian context, recent innovations have occurred outside the domain of the ANZCTR. These include the use of apps for patient recruitment and the development of an integrated data-set, National Aggregate Statistics (NAS), to generate performance metrics on key indicators including timeliness of ethics committee approval and site authorisation. Of relevance to the ANZCTR, some observers of the Australian context have raised the prospect of streamlining the range of data reporting requirements to reduce reporting burden and enable the registry’s integration within a ‘one-stop shop’ to support clinical trials reporting and governance.

1.3 Performance assessmentBased on the review of ANZCTR’s role in the context of WHO requirements, best practice developments in other jurisdictions, feedback from stakeholder consultations and workshops with the sector, it is apparent that there are several issues confronting the ANZCTR. These have been encapsulated into five broad themes or ‘problems’:

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The registry has incomplete coverage and inconsistent data quality; The registry is not easy to use; Trial results are not reported to the registry; There is a lack of integrated performance metrics and system inter-operability; and The registry lacks strategic governance.

Key benefits that would flow from addressing these problems include: Improved research transparency; Avoided duplication of research; Improved patient recruitment; Improved sector efficiency and value for money; and Improved accountability of the registry

Importantly, the first three of these benefits are consistent with the current role and purpose of the registry. The last two benefits are new priorities for future development.

Figure 1-1 shows schematically that the achievement of these benefits relies upon a range of strategic responses.

Figure 1-1: Investment logic map

Incomplete coverage &

inconsistent quality

Not easy to use

Results are not reported

Lack of integrated performance

metrics

Lack of strategic governance

Research transparency

Improve patient recruitment

Improve sector efficiency & value

for money

Improve accountability

Problem Benefit Strategic response

Improve registry coverage & data

quality

Improve IT search & navigation functions

Enable results to be reported

‘One-stop shop’ with KPIs & streamlined

reporting

Strengthen governance

Avoid duplication of research

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1.4 Strategic responses & optionsStrategic responses under each option are summarised and depicted in Figure 1-2 .

Figure 1-2: Depiction of options

It is apparent that options 1 to 3 are sequential, with each building upon the preceding option. The fourth option, disinvestment, is not a recommended option.

Underpinning options 1 through 3 is the common requirement for strengthened governance. This could be achieved by: Revising the terms of reference and reconstituting the governance committee; Assigning the Board of Management with defined milestones for implementation of the review

recommendations; Constituting a 10 to 12-member Reference Group to enable continued stakeholder engagement;

and Providing transparent and formalised future governance arrangements via public annual reporting.

Option 1 aims to increase coverage and improve data quality and currency by:

Developing tighter reconciliation processes with ethics committees; Developing exception reports to identify approved clinical trials that are not registered; Including regular data feeds to the ANZCTR of Australian trials in other WHO Primary Registries; Including a provision in the National Statement for coordinating principal investigators to provide

evidence to ethics committees that a trial is up-to-date on ANZCTR as part of the annual review; Implementing targeted, repeat notifications to increase the proportion of trials updated annually; Implementing audits to identify characteristics out of date records; and Implementing KPIs for currency and making these (de-identified) results publicly available.

Option 2 builds on from Option 1 and adds the inclusion of results and protocols by:

Developing IT enhancements to allow for results to be reported as a mandatory field; and

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Reviewing the feasibility of adopting standards for electronic protocol reporting as a mandatory field for publicly funded trials initially.

Option 3 encompasses both Options 1 and 2, while also enabling the registry’s integration within a one-stop shop with performance metrics, concierge support, and streamlined reporting by:

Developing IT interoperability enhancements for incorporation of performance metrics; Reviewing the feasibility for streamlined data feeds between ANZCTR and other systems; and Redeveloping the ANZCTR hotline with a dedicated concierge function.

1.4.1 DISINVESTMENT OPTION

The option of disinvestment and reliance on ClinicalTrials.gov was considered and would effectively result in the cessation of the ANZCTR. The advantages put forth for this option were: It is the simplest way to avoid duplication; Many industry-driven trials already use ClinicalTrials.gov; and FDA mandates registration on ClinicalTrials.gov for prospective approval in the US

pharmaceuticals market.

Conversely, several disadvantages were identified: It would not be attuned to the local Australian context; It would complicate promotion of local participation in clinical trials; ClinicalTrials.gov is limiting registration requests from other regions; There would be no scope for integrated performance metrics; and Australia would have no influence on the strategic direction of the registry nor its governance.

The disinvestment option is not recommended.

1.4.2 IMPLEMENTATION TIMEFRAME

Indicative implementation timeframes for each option are outlined in Figure 1-3.

Figure 1-3: Implementation timeframes by option

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2 Context and purpose

2.1 Context

Aspex Consulting has been engaged by the Australian Government Department of Health to undertake an independent review of the Australian New Zealand Clinical Trials Registry (ANZCTR).

Clinical trials play a pivotal role in research and development of new treatments, drugs, devices and tests.1 They are fundamental to driving progress in models of care and advancing quality and safety in health care. Economically, the breadth of the clinical trials undertaken in Australia is substantial and represents a key employer of highly skilled workforce.2 Continued growth of clinical trials is directly aligned with government policy with major investments through the National Innovation and Science Agenda and through the Medical Research Future Fund.

In turn, clinical trial registries are fundamentally important to the research endeavour. They facilitate access by research to the research community and more broadly to health care decision-makers. By promoting transparency, this helps to overcome publication bias and selective reporting, and ultimately strengthens the validity and value of the evidence base.3

For consumers, the value of accessible, easy to navigate and easy to comprehend information from clinical trial registries has many benefits. It can facilitate improved understanding of clinical trials4 and there is some evidence it offers the opportunity to access best clinical management.5

Through the Council of Australian Governments (COAG), jurisdictions and the Commonwealth are collaborating on a revitalised clinical trial agenda, to improve the Australian clinical trials environment with a view to improving health outcomes and increasing international investment in Australia. A key part of these efforts will be strengthening national clinical trials infrastructure.

The ANZCTR is an online public registry of clinical trials, held at the National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, and together with the US-based ClinicalTrials.gov, is one of the two main registries used in Australia.6 It currently underpins the national Australian clinical trials website (www.australianclinicaltrials.gov.au), a joint initiative between the NHMRC and the Department of Industry, Innovation and Science (DIIS), which provides information and resources to consumers, patients and clinicians about clinical trials and aims to facilitate recruitment into clinical trials.

The ANZCTR is a critical component of national clinical trial infrastructure, and part of the worldwide initiative to make public all clinical trials being conducted. Trial registration 1 NHMRC, Clinical Trials, https://www.nhmrc.gov.au/research/clinical-trials2 MTPConnect, June 2017, Clinical trials in Australia: the economic profile and competitive advantage of the sector.3 WHO, International Clinical Trials Registry Platform4 Dear R et al., 2011, Adding value to clinical trial registries: insights from Australian Cancer Trials Online, a website for consumers. Clin Trials.

Feb;8(1):70-6. 5 Clinical trial management, PC4, http://pc4tg.com.au/our-services/clinical-trial-registration/6 Although the registry is held at the NHMRC CTC, the CTC is not a formal NHMRC entity

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through ANZCTR has the potential to improve research transparency, facilitate trial participation, avoid research duplication, identify research gaps, and promote collaboration.

A recent report commissioned by the Department of Health (the Department) on behalf of the then Clinical Trials Jurisdictional Working Group (CTJWG) (now Clinical Trials Project Reference Group – CTPRG) recommended that jurisdictions and the Commonwealth collaborate to identify opportunities to improve the ANZCTR’s relevance for participants and researchers and ensure it is regularly updated.

2.2 Purpose

The purpose of the current ANZCTR review is to:

1. Identify best practice approaches for contemporary international and domestic clinical trial registries through a literature review and jurisdictional scan;

2. Assess the current performance, appropriateness and value for money of the ANZCTR, including current users and uses, and the extent that current services are meeting the needs of stakeholders and aligned to contemporary international and domestic best practice for clinical trial registries;

3. Provide recommendations (three fit-for-purpose options) regarding improvements, costs, risks and mitigation strategies, and a likely transition timeframe and process of potential next generation Australian clinical trial registry.

4. The focus of the review is on the Registry’s role and function, it is not a review of the management or governance of the ANZCTR.

An overview of the project components is summarised in Figure 2-1.

Figure 2-4: Project methodology

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Project establishment and work plan

Jurisdictional scan and literature review

Development of evaluation criteria

Stakeholder discussion guide

Stakeholder consultations

Options analysis

Workshop

Draft report

Final report



3 Current arrangements

This section describes current arrangements. It summarises the ANZCTR’s current role, key outputs, organisational links to other registries, the operational context – financial, workforce and IT – and governance.

3.1 Current role

ANZCTR describes its current role as follows:

Improve research transparency: Making details of all trials publicly available improves research transparency and helps to overcome publication bias and selective reporting, thereby enabling clinicians and consumers to make more informed decisions;

Facilitate trial participation: People interested in participating in a clinical trial and doctors investigating relevant trials for their patients have access to a reputable and comprehensive on-line register showing what trials are occurring across all areas of health, which may facilitate recruitment;

Avoid duplication: Improving awareness of similar or identical trials will make it possible for researchers and funding agencies to avoid unnecessary duplication;

Identify potential research areas: Describing clinical trials that are planned, in progress, and recently completed, can make it easier to identify gaps in clinical trials research;

Promote research collaboration: Enabling researchers and health care practitioners to identify trials in which they may have an interest could result in more effective collaboration among researchers; and

Improve trial quality: Registries checking data as part of the registration process may lead to improvements in the quality of clinical trials by making it possible to identify potential problems (such as problematic randomisation methods) early in the research process.7

3.2 Key functions

The ANZCTR’s key functions can be segmented into firstly, core activities and secondly, research and development. These are described in more detail below. The resource requirements to support these functions are described in section 3.3 and governance in section 3.4.

3.2.1 CORE ACTIVITIES

The ANZCTR’s core activities reflect compliance requirements of the International Standards for Clinical Trial Registries.8 The Standards comprise six areas:

Content;

Quality and Validity;

7 ANZCTR, Frequently Asked Questions, What is the purpose of the ANZCTR and why it is important? http://www.anzctr.org.au/Faq.aspx8 ICTRP, 2012, International Standards for Clinical Trial Registries, World Health Organisation.

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Accessibility;

Unambiguous identification;

Technical capacity; and

Administration and governance.

Consistent with the requirements of the Standards, the ANZCTR has prepared Standard Operating Procedures, that describe how it operationalises these standards.

A description is provided below of the core activities that ANZCTR undertakes to fulfil its role in relation to each of the Standards.

(i) Content

WHO requirements

In terms of content, WHO expects that primary registries will:

Accept prospective registration of interventional clinical trials submitted by Responsible Registrants;

Be open to all prospective registrants (ICMJE) internationally or within one or more specific countries;

Be able to collect and publicly display the WHO Trial Registration Data Set (ICMJE) with registries able to choose to make all 20 items mandatory before they accept registration;

Endeavour to keep registered information up-to-date; and

Never remove a trial once it has been registered.

ANZCTR approach

The ANZCTR’s core role is to facilitate online registration of clinical trials for registrants who are seeking to either prospectively or retrospectively register trials. In the 2017 calendar year there were 1,651 studies registered by ANZCTR.

ANZCTR report that the majority (60%) of clinical trials that are recruiting in Australia are registered on ANZCTR with 35% on ClinicalTrials.gov and 5% on other sites including ISRCTN.org, German CTR and EU-CTR.

Clinical trials with Australian and New Zealand recruitment sites registered on ClinicalTrials.gov are also displayed on the ANZCTR. Data from ClinicalTrials.gov are imported and mapped to the corresponding ANZCTR field (where possible) for display on the ANZCTR. There are several ANZCTR fields for which data is either not available on the ClinicalTrials.gov record or cannot be extracted. The primary sponsor or an authorised representative of the primary sponsor for the trial registered with ClinicalTrials.gov can provide details for these additional ‘missing’ fields through the ANZCTR.9

9 ANZCTR, FAQs, http://www.anzctr.org.au/Faq.aspx#g1 accessed 18 May 2018

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http://www.anzctr.org.au/Faq.aspx#g1



From late May 2018, registrants will be able to add additional ANZCTR specific information and local contact details to records from ClinicalTrials.gov if they wish, without the need to apply for an ANZCTR registration number as well.10

Accept prospective registration of interventional trials ANZCTR accepts prospective registration. It states that a study can be submitted for

registration before or after ethics committee approval has been obtained. If a study is registered before receiving ethics approval, a ‘Provisional’ watermark label appears on the record;

Between 65% to 70% of ANZCTR trials are prospectively registered;11

ANZCTR accepts both interventional and observational trials.

Open to one or more specific countries The ANZCTR may be used to register clinical trials from Australia and New Zealand.

Whilst the ANZCTR prioritises submissions from Australian and New Zealand registrants and trials with recruitment sites in Australia or New Zealand, there is scope for registration from other international registrants. However, ANZCTR advises prospective registrants that international trial registrations may encounter delays in processing a trial submission and that additional time should be allowed prior to enrolment of the first participant.

Able to collect and display the WHO Trial Registration Data Set The ANZCTR enables the collection and public domain display of the 20 data fields Trial

Registration Data Set. ANZCTR stipulates that there is a mandatory requirement for registrants to enter data in 20 of the 20 data fields as summarised in Table 3-1.

Table 3-1: List of data items required by the WHO

NO. DATA ITEM MANDATORY OR DISCRETIONARY

1. Primary registry and trial identifying number Mandatory2. Date of registration in Primary registry Mandatory3. Secondary identifying numbers Mandatory4. Source(s) of material support Mandatory5. Primary sponsor Mandatory6. Secondary sponsor Mandatory7. Contact for public queries Mandatory8. Contact for scientific queries Mandatory9. Public title Mandatory10. Scientific title Mandatory11. Countries of recruitment Mandatory

10 ANZCTR, NEWS, http://www.anzctr.org.au/News.aspx, accessed 18 May 201811 Askie LM, Hunter KE, Berber S et al. 2017, The clinical trials landscape in Australia 2006–2015, Australian New Zealand Clinical Trials Registry:

Sydney, p.50

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http://www.anzctr.org.au/News.aspx



NO. DATA ITEM MANDATORY OR DISCRETIONARY

12. Health condition(s) or problem(s) studied Mandatory13. Interventions Mandatory14. Key inclusion and exclusion criteria Mandatory15. Study type Mandatory

16. Date of first enrolment12 Mandatory

17. Target sample size Mandatory

18. Recruitment status Mandatory

19. Primary outcomes Mandatory

20. Key secondary outcomes Mandatory

The ICTRP standards have listed an additional three data items that are optional items for collection at the time of registration. As shown in Table 3-2, two of these three items are designated by the ANZCTR as mandatory fields. The third item, results links, is a field that provides for links to citations of publications as well as links to results databases, conference proceedings, registry results sections and other links relevant to results. This field is available in the ANZCTR ‘Trial related presentations / publication list’.

Table 3-2: Additional items for collection at time of registration

NO. DATA ITEM MANDATORY OR DISCRETIONARY OR FIELD NOT AVAILABLE

21. Lay summary/synopsis Mandatory

22. Approvals Mandatory

23. Results links Discretionary

Endeavour to keep registered information up-to-date ANZCTR enables registrants to update the registry over time.

In 2014, the ANZCTR introduced a system refinement in which automated reminders are sent to registrants to update the clinical trial record. Once updated, records are flagged with an ‘up-to-date’ status on the front view page of the registration record. Since the introduction of this change, between 55% to 60% of registered trials are updated each year.

The ANZCTR has identified currency of information reported to the registry as a substantial challenge. This stems from the absence of direct incentives or sanctions that can be applied to registrants. In other jurisdictions, ANZCTR highlights that regulatory requirements provide a stronger inducement for registrants to provide updates. These include provisions by which ethics committees require evidence of an up-to-date trial

12 Anticipated date is mandatory if recruitment has not started; Actual date is mandatory once recruitment has started. ANZCTR, SOPs, 2017, p. 163

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registration record as part of the annual ethics committee update or in which regulatory sanctions, including financial penalties, may apply for non-adherence.

Never remove a trial once it has been registered The ANZCTR retains trials on the registry. Since its establishment in 2005 and by the

start of December 2017, 14,809 trials had been registered on the ANZCTR.

This requirement is stated publicly on the ANZCTR website: “Once a study has been registered, it cannot be removed and remains publicly viewable.”13

(ii) Quality and validity

WHO requirements

Primary registries will:

Have a mechanism in place to ensure the validity of the registered data (ICMJE);

Have processes in place to maximize the possibility that the data registered is complete and accurate. These processes should be documented as Standard Operating Procedures (SOPs). This will include processes to make certain that:

the person registering the trial exists and is the appropriate Responsible Registrant

the trial exists the data submitted is complete

It is the responsibility of the Responsible Registrant to make sure that the data provided to the Registry is complete and accurate;

Maintain a publicly accessible audit trail so changes made to the WHO Trial Registration Data Set for an individual trial can be tracked; and

Participate in the development of WHO Best Practice Guidelines for Clinical Trial Registries.

ANZCTR approach

ANZCTR staff undertake a check of all submitted data to ensure all WHO dataset requirements are met before allocation of a registration number. Data are also checked for clarity and consistency, validity, logic and formatting.

Each year the ANZCTR undertakes audits of data quality. This involves a 5% sample of trial records with each record reviewed to determine whether the data in the data field met the criteria required for Primary Registries in the WHO Registry Network and ANZCTR-specific requirements detailed in the ANZCTR’s “Data Item Definition/Explanation” document. In 2017, the audit found that 100% of sampled records met the audit criteria and in 2016 99% of sampled records met the audit criteria.14

The ANZCTR has a publicly accessible audit trail of all changes that are made to all details of clinical trials reported to the registry.

13 ANZCTR, FAQs, http://www.anzctr.org.au/Faq.aspx#g1, accessed 18 May 201814 ANZCTR, Data completeness and quality audit, 2016 and 2017.

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ANZCTR has been an active contributor to standards development for the ICTRP and Lisa Askie, Manager, ANZCTR, co-authored the 2012 International Standards for Clinical Trial Registries and has been represented on the Best Practice Group.

The schematic below summarises the processes entailed in trial registration and updates inclusive of the checking processes prior to registration and at the time of registry updates.15

The ANZCTR states explicitly on its website that the registrant is responsible for ensuring that the information provided in the registration record remains accurate and up-to-date. It provides updating instruction on its website.16

Figure 3-5: Process map of ANZCTR trial registration and update steps

Registrant submits form online

ANZCTR staff check +/- query submitted data Changes or additional information required

No changes or additional information required

Trial registered. ACTRN assigned Query email sent Registrant amends & resubmits

Update required

Update reminder email sent

Registrant enters updated information online & submits form

ANZCTR staff check +/- query submitted data Changes or additional information required

No changes or additional information required

Updates approved and become publicly viewable Query email sent Registrant amends & resubmits

Regi

stra

tion

Upda

ting

15 Adapted from Askie LM, Hunter KE, Berber S et al. 2017, The clinical trials landscape in Australia 2006-2015, ANZCTR, page 5516 ANZCTR, How to update a trial, http://www.anzctr.org.au/support/HowToUpdate.aspx, accessed 18 May 2018

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http://www.anzctr.org.au/support/HowToUpdate.aspx



Accessibility

WHO requirements

Primary registries are expected to:

Ensure that the WHO Trial Registration Data Set for all registered trials will be:

Accessible to the public at no charge (ICMJE) Electronically searchable (ICMJE) Made available to the ICTRP in English;

Allow registrants to submit a trial for registration at any time of day on any day of the week (24 hours a day, seven days a week);

Allow the register to be searched at any time of day on any day of the week (24 hours a day, seven days a week); and

It is desirable that Primary Registries in the WHO Registry Network also make the WHO Trial Registration Data Set available in the language(s) of the country or countries served by the registry.

ANZCTR approach

The ANZCTR is a public domain, online resource that is available for data entry or data search 24 hours per day, 7 days a week. No user charges are applied to register trials.

ANZCTR monitors website usage through Google Analytics. Monthly usage increased from around 7,000 visits per month in 2011 to 15,000 per month in 2015. However, monthly usage in 2017 is estimated to have reduced to approximately 9,600 per month.

The ANZCTR website has simple and advanced search functions. ANZCTR also offers tailored assistance, subject to its available resources, to assist users with specific more detailed searches. These are undertaken relatively frequently, around once a week.

To streamline the registration process and reduce the number of user queries, the ANZCTR has automated a substantial component of the registration and updating process. These IT refinements include the use of drop-down menus and pick-lists (in place of free text fields) and the introduction of logic rules in September 2016. Subsequent to the introduction of logic rules, there has been a reduction of registry updates that require staff response to queries from 55% to 37%.

The ANZCTR undertakes regular reviews of the user profiles who access the ANZCTR and seeks their reviews on the relative ease of use of the registry and its relevance. As would be expected, the largest category are registrants who comprised over one third (36%) in 2016, with researchers/systematic reviewers just over one quarter (26%) and consumers about one fifth (21%), as shown in Table 3-3.17

17 ANZCTR, 2017, Australian New Zealand Clinical Trials Registry (ANZCTR) user survey results from 2016-2017

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Table 3-3: Type of ANZCTR user, 2009 to 2016TYPE OF ANZCTR USER 2009 2014 2016

Registrant 31% 27% 36%

Researcher/systematic reviewer 24% 29% 26%

Consumer (patient, relative, friend) 18% 21% 21%

Journal editor/staff 3% 2% 2%

Funder 2% 2% 1%

Regulator 1% 1% 1%

Clinician 11% 10% 10%

Other 10% 8% 3%

A greater proportion of registry users report that they find it easy to find information on the registry, up from 56% in 2009 to 69% in 2016-17. A similar trend is observed in response to ease of navigation of the registry website, as shown in Figure 3-6.18

Figure 3-6: User perceptions of the ANZCTR, 2009 to 2016-17

0%

10%

20%

30%

40%

50%

60%

70%

80%

Finding the information I need on the ANZCTR is easy The ANZCTR website is easy to navigate

2009 2014-15 2016-17

ANZCTR requires that all submissions be written in clear and concise English and that where this is not the case it may exercise the right to reject the submission.19

Unambiguous Identification

18 ANZCTR, 2017, Australian New Zealand Clinical Trials Registry (ANZCTR) user survey results from 2016-201719 ANZCTR, FAQs, http://www.anzctr.org.au/Faq.aspx#g1, accessed 18 May 2018

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WHO requirements

Primary registries will:

Have in place processes to prevent the registration of a single trial more than once on their database;

Facilitate the retrospective linking (or bridging) on the WHO Search Portal of a single trial registered with more than one registry by entering secondary identifiers. This includes the Universal Trial Number (UTN), and the unique identifiers allocated by other Primary Registries in the WHO Registry Network; and

It is desirable that Primary Registries in the WHO Registry Network as part of the registration process, search the ICTRP Search Portal and attempt to determine if the trial has already been registered by another Primary Registry or an ICMJE approved registry.

ANZCTR approach

ANZCTR standard operating procedures specify the procedures by which ANZCTR staff undertake a search of the ANZCTR in advance of registration of a clinical trial to seek to limit the potential that a trial might be registered more than once. Similarly, ANZCTR staff search the ICTRP Search Portal to seek to ascertain whether a trial has been registered on ClinicalTrials.gov or another Primary Registry.

ANZCTR has the capacity to enter secondary identifiers, including the UTN and unique identifiers allocated by other Primary Registries in the WHO Registry Network.

ANZCTR periodically audits the registry to assess the rate of duplicate trial registrations. It has undertaken nine audits since 2006 to 2017 with two audits undertaken in the last five years, in 2013 and in 2017. The 2017 audit reviewed trials registered in the period 2013-2017 and found that the proportion of duplicate trial records was extremely low at 0.06%.20

A relatively small number of multi-site trials, estimated to be 1% of all trial registrations in Australia, are registered on both the ANZCTR and ClinicalTrials.gov. This may be an under-estimate of duplicate entries as there may be trials registered on both registries which do not cross-reference both registration identification numbers in the records of both registries.

Technical Capacity

WHO requirements

Primary registries are expected to comply with a range of technical capacity criteria. This requires that they:

Submit the WHO Trial Registration Data Set for all records on their registry, in English, to the Central Repository;

Have access to a database that is used to store and manage the submitted data:

Primary registries are not required to develop their own database. See the Data Providers section for more information;

20 ANZCTR, Trial Duplication Data Audit 2006-2017: Results

21



Be able to demonstrate that they have access to adequate information technology support; and

Have adequate security and other provisions against data corruption and loss.

ANZCTR approach

ANZCTR supplies a weekly feed of data from the registry to the WHO ICTRP.

The IT infrastructure supporting the ANZCTR software appears to be fit-for-purpose based on the hardware specifications of the web server and application server. The CTC data centre has appropriate environmental controls in place to protect the IT infrastructure from loss of power, cooling and telecommunication services.

Physical and data security measures appear to be appropriate, however it is difficult to comment further on access controls (exactly who has access to the environment and how well it is controlled). Nor is it possible to assess the effectiveness of the security firewall without direct investigation of its configuration and currency.

The registry appears to be a prime candidate for migration to a Cloud environment as a means of controlling cost and currency of the associated infrastructure and simplifying management of its availability and assuring business continuity.

Further details on the current IT infrastructure relevant to the ANZCTR are provided as Appendix 3.

Administration and Governance

WHO requirements

Robust administration and governance processes require that primary registries will:

Have at least a national remit, and the support of government within the country (or region) to act as the WHO Primary Registry for that country (or region)

All WHO Primary Registries are required to provide a letter of support from the Ministry of Health or other relevant national or regional agency;

Publicly disclose ownership, governance structure and not/for-profit status;

Be managed by a not-for-profit agency (ICMJE);

Should a registry cease to function the registry agrees that at least the WHO Trial Registration Data Set (original and updated) for all trial records will be transferred to a Primary Registry in the WHO Registry Network or appropriate alternative; and

It is desirable that Primary Registries in the WHO Registry Network have a strategy in place addressing the medium to long term sustainability of the registry.

22



ANZCTR approach

ANZCTR has a national remit. The ANZCTR is identified in the Australian Government’s 2016 National Research Infrastructure Roadmap as the “national registry and an integral part of the World Health Organisation’s International Clinical Trials Registry Platform”.21

The ANZCTR states on its website that it is “publicly owned, managed by a not-for-profit organisation.”22

There is an Advisory Committee for the ANZCTR with provision for up to 11 members. Membership is intended to include individuals with strong contacts with the clinical research communities throughout Australia and New Zealand. The 2017 members of the Advisory Committee are listed in Table 3-4.

Table 3-4: ANZCTR Advisory Committee membership

NAME ORGANISATIONProf Judith Whitworth Chair, ANZCTR Advisory Committee

Prof John Simes Chief Investigator A on the ANZCTR NHREC Grant

Prof Brendan Murphy Chief Medical Officer of Australia

Prof John Skerritt Deputy Secretary for Regulatory Services, Department of Health

Prof Ian Olver Representative of the Australian Health Ethics Committee

Mr Tony Krizan Representative of the NHMRC

Ms Erica Kniepp Representative, Department of Health (Assistant Secretary, Health and Medical Research)

Ms Lucy Pomeroy Representative for the Health Research Council of New Zealand

Prof Paul Glasziou Representative of the Clinical Research Community (Professor of Evidence-Based Medicine, Bond University)

TBA Industry representative (Medicines Australia)

Mr John Stubbs Health consumer representative

Prof Nicholas Talley Editor of an ICMJE affiliated medical journal (Editor in Chief, Medical Journal of Australia)

Dr Rebecca Halligan Nominee of the University of Sydney independent of the ANZCTR project, (Director of Research Integrity and Ethics Administration, University of Sydney)

The role of the ANZCTR Advisory Committee is to provide the ANZCTR Management with strategic advice in relation to the operation and development of the ANZCTR.23 Specifically, the terms of reference state that ANZCTR Advisory Committee shall provide advice on the following matters:

The operation of the ANZCTR, having regard to consumer, industry and government perspectives;

Accessibility of information contained in the ANZCTR;

21 Australian Government, 2016, National Research Infrastructure Roadmap, Australian Government, p.7522 ANZCTR, About us, http://www.anzctr.org.au/Support/AboutUs.aspx, accessed 18 May 2018.23 ANZCTR Advisory Committee Terms of Reference, ANZCTR

23

http://www.anzctr.org.au/Support/AboutUs.aspx



The scope of clinical interventions to be included in the ANZCTR;

Process(es) for the mandatory registration of clinical trials;

Treatment of commercially sensitive information;

The minimum data set for the registry;

Review of the ANZCTR;

Issues affecting the long-term sustainability of the ANZCTR;

International obligations/links; and

Other matters relevant to the operation and development of the ANZCTR or the Advisory Committee, as may be requested by the NHMRC (through its appropriate committees) or the TGA.

Unusually, the terms of reference state that “the ANZCTR Advisory Committee reports to the ANZCTR Management.”

The meeting frequency is low with the terms of reference stating that “The ANZCTR Advisory Committee will hold one face-to-face meeting per year. Additional smaller working groups may be arranged if required.”

Although ANZCTR has not developed strategic plans in the last five years, it has recently developed a business case which sets out strategic future options for the registry.24

3.2.2 RESEARCH AND DEVELOPMENT

In addition to its core functions, the ANZCTR undertakes a range of research and development activities. Recent examples include:

Developing complementary strategies to broaden access to the registry;

Undertaking periodic research and analysis of the registry;

Enhancing the functionality of the registry; and

Collaborating on further development of clinical trial registries worldwide

These are described briefly below.

Developing complementary strategies to broaden access to the registry

Two recent strategies have broadened access to the registry.

As an initiative of the Department of Industry, Innovation and Science (DIIS) and the NHRMC, the website australianclinicaltrials.gov.au was developed to provide a more user-friendly and accessible basis for those seeking to find out information about clinical trial. This website receives regular data feeds from the ANZCTR.

24 ANZCTR, Business Case for the ongoing support of the Australian New Zealand Clinical Trials Registry (ANZCTR), 19 February 2018

24



ANZCTR provides support to Cancer Australia’s website, australiancancertrials.gov.au and assists in the provision of plain English descriptions of cancer trials. The aim of this is to improve the ease of access by consumers to information about clinical trials relevant to cancer.

Undertaking periodic research and analysis of the registry

The most recent example of research and analysis of the registry is The Clinical Trial Landscape in Australia 2006-2015.25 This involved a review of trends over time in registrations to the ANZCTR as well as Australian trials registered on ClinicalTrials.gov. It provides an overview of:

trial activity, including the number and types of trials, numbers of participants, how Australia compares internationally, sponsor type and industry involvement;

trial focus including conditions and how these compare to population burden of disease, intervention type and trial design including trends in sample size; and

trial registration including share of prospectively registered trials, and time between registration and start of enrolment.

There have also been numerous publications and conferences papers completed since 2015 by the ANZCTR (see Appendix 5).

Enhancing the functionality of the registry

Enhancements to the functionality of the registry, implemented or developmental, in the last three years include:

IT enhancements to automate registration – as discussed above, the inclusion of drop-boxes and logic rules has reduced the number of queries submitted by users for staff assistance;

Enabling the inclusion of trial registration details from ClinicalTrials.gov to be incorporated within the ANZCTR, with the facility in late May 2018 for additional trial details to be reported to ANZCTR including details of principal investigators and details of Australian trials sites;

In collaborative work with Canada, development of protocols using SEPTRE (SPIRIT Electronic Protocol Tool & Resource) to enable the inclusion of trial protocols. This developmental work seeks to promote the potential for research protocols to be included on the registry, thereby enabling scope for open access to protocols and enabling trial reproducibility.

Collaborating on the further development of clinical trial registries worldwide The ANZCTR was a key author of the International Standards for Clinical Trial Registries

and a member of the Best Practice Group of the ICTRP.

The focus of most ANZCTR publications and conference papers has been on enhancements to clinical trial registries.

25 Askie LM, Hunter KE Berber S et al. 2017, The Clinical Trial Landscape in Australia 2006-2015, Sydney, Australian New Zealand Clinical Trial Registry

25



3.3 Operational context

Workforce trends by staffing category are analysed in sub-section 3.3.1 followed by an analysis of income and expenditure over the last five years.

3.3.1 WORKFORCE

The staffing complement for the ANZCTR is summarised in Table 3-5 below and the relative share in percentage terms is summarised in Table 3-6. It can be seen that on average, over the five-year period, the ANZCTR management of the registry required 0.50 FTE or 9% of the total FTE, senior project staff and other project staff accounted for 2.36 FTE (42%), IT staff made up 1.69 FTE (32%) and research fellows 0.16 FTE (13%).

Table 3-5: Staffing profile for the ANZCTR, 2013 to 2017

STAFF CATEGORY 2013 2014 2015 2016 2017 Five-year average

Management 0.45 0.45 0.45 0.54 0.60 0.50

Senior project officer/project officer 2.40 1.00 2.39 2.59 3.41 2.36

Senior IT officer/IT officer 1.80 1.61 1.74 1.60 1.72 1.69

Research fellow 0.60 0.48 0.60 0.48 1.66 0.76

Executive support 0.20 0.20 0.10 0.10 0.20 0.16

Total 5.45 3.74 5.27 5.31 7.59 5.47

Table 3-6: Relative share of FTE by staff category, ANZCTR, 2013 to 2017

STAFF CATEGORY 2013 2014 2015 2016 2017 Five-year average

Management 8% 12% 8% 10% 8% 9%

Senior project officer/project officer 44% 27% 45% 49% 45% 42%

Senior IT officer/IT officer 33% 43% 33% 30% 23% 32%

Research fellow 11% 13% 11% 9% 22% 13%

Executive support 4% 5% 2% 2% 3% 3%

Total 100% 100% 100% 100% 100% 100%

From Figure 3-7 it can be seen that there has been a substantial increase in project officer and research fellow resourcing (FTE) in 2017. ANZCTR have identified that the increase in FTE in 2017 is due to the additional staffing required for time-limited projects, the largest of which was the analysis required for the ANZCTR publication, The Clinical Trials Landscape in Australia, 2006-2015.

26



Figure 3-7: Trend in FTE by staff category, ANZCTR, 2013 to 2017

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

2013 2014 2015 2016 2017

FTE

Management Project officers/Senior project officer

IT/Senior IT Research fellow

Executive support

The FTE for 2017 is further disaggregated by core staff and one-off project staff based on advice from ANZCTR on staffing functions for the most recent calendar year. It is apparent that overall staffing at 5.58 FTE for core staff is close to the five-year average of 5.47 FTE. Core project staffing levels are 2.78 in 2017 compared to 2.38 over the five years; IT core staffing at 1.0 FTE is lower than the five-year average of 1.69 FTE and core research FTE is slightly higher at 1.0 FTE relative to 0.76 for the five-year average. Management is slightly higher in 2017 (0.6 FTE) relative to 0.5 for the five-year average and executive support is largely the same (0.20 relative to a five-year average of 0.16).

Table 3-7: FTE breakdown by core and one-off staff, ANZCTR, 2017

STAFF CATEGORY 2017 Core 2017 One-off 2017 Total 5 Year Average

Management 0.60 0.00 0.60 0.50

Project officers/Senior project officer 2.78 0.63 3.41 2.36

IT/Senior IT 1.00 0.72 1.72 1.69

Research fellow 1.00 0.66 1.66 0.76

Executive support 0.20 0.00 0.20 0.16

Total 5.58 2.01 7.59 5.47

27



Key functions for the main staffing categories are summarised below:

Project Officers

Key functions performed by project officers include the following:

Oversee the daily operational and technical management of the ANZCTR and implement strategic priorities/plans of the ANZCTR;

Assess and register clinical trials with complete and accurate information, according to the dataset requirements (per World Health Organization [WHO] and International Committee of Medical Journal Editors [ICMJE] standards and criteria);

Review and assess the data submitted by ANZCTR registrants for accuracy and completeness;

Provide information to members of the public, medical and research professions, patients, consumers and others via an information telephone hotline, email and written enquiries;

Actively encourage stakeholders to adopt and use the ANZCTR as appropriate for their needs by promoting the importance of trial registration and liaising with a diverse range of stakeholders regarding data sharing and other potential collaborative projects;

Develop and maintain quality assurance processes including Standard Operating Procedures and ensure that these processes and procedures are applied by the team;

Prepare and deliver educational and training materials for internal and external presentations featuring ANZCTR project objectives, outcomes, and updates;

Generate, collate, analyse and report on monthly website statistics for the ANZCTR, and for the Australian Cancer Trials website on behalf of Cancer Australia, as well as any other documentation and data analysis reports in relation to ANZCTR;

Identify problems/glitches with the ANZCTR website/database as they arise, and/or test possible solutions with dedicated ANZCTR IT staff member(s); and

Conduct collaborative research projects.

IT staff

Key functions performed by IT staff include the following:

Plan and implement ANZCTR database and website developments;

Undertake acceptance testing of Clinical Trial Management Software;

Develop other clinical trial related databases and websites;

Implement data sharing capabilities with external collaborators; and

Optimise and monitor website performance.

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4 Findings from literature review and jurisdictional scan

This section presents highlights of the literature review undertaken to explore the role and purpose of clinical trial registries and emerging trends together with findings from a jurisdictional scan of clinical trial registries in the US, Europe and the UK. A full report of the literature and jurisdictional scan has been separately prepared.

4.1 Definitions

A clinical trials register is the formal record of an internationally agreed minimum amount of information about a clinical trial. This record is usually stored in and managed using a database. A clinical trials registry is the entity that houses the register and is responsible for ensuring the completeness and accuracy of the information it contains.

4.2 Role and purpose

The WHO promotes registration of clinical trials in order to:

Enable decisions about health care to be informed by the available evidence;

Promote transparency and reduce the risk of publication bias26 and selective reporting;

Build awareness of similar or identical trials, limiting the likelihood that research is duplicated;

Determine gaps in clinical trials research by enabling access to information on trials;

Promote awareness of the range of clinical trials which are recruiting to facilitate recruitment for researchers and potential participants; and

Enhance the quality of clinical trials through data checking at the point of trial registration.

The stated role and purpose of the ANZCTR registry aligns with the above WHO rationale.

Under the Australian Government 2016 National Research Infrastructure Roadmap, the ANZCTR is described as Australia’s ‘national registry’. It is one of 15 Primary Registries recognised by the WHO’s International Clinical Trials Registry Platform. WHO accreditation requirements cover a range of compliance areas including content, quality and validity, accessibility, unambiguous identification of trials, technical capacity, administration and governance.

4.3 Policy and funding context

The ANZCTR sits within a complex policy and funding landscape. Along with market participants, multiple bodies shape the sector, including government agencies, government affiliated entities at state, territory and federal level, not-for-profit organisations and health associations. Figure 4-8 provides a visual representation of the policy and funding context.

26 ‘Publication bias’ refers to the publication or non-publication of research findings, depending on the nature and direction of the results. Cochrane Methods, Reporting Biases, http://methods.cochrane.org/bias/reporting-biases accessed 18 March 2018.

29

http://methods.cochrane.org/bias/reporting-biases



Figure 4-8: Policy and funding map for ANZCTR

ANZCTR

WHOICMJEClinical Trials.govAustralianClinicalTrials.gov.auClinTrial Refer

States and Territories

CTPRG

Commonwealth of Australia

Department of HealthDepartment of Education and Training

Department of Innovation, Industry and Science

NHMRCNCRIS, TIA

INTERGOVERNMENTAL COORDINATION

COMPLIANCE & DATA SHARING

Council of Australian Governments (COAG)

COAG Health Council(AHMAC)

CPC

MRFF

MRFF: Medical Research Future FundNCRIS: National Collaborative Research Infrastructure StrategyNHMRC: National Health and Medical Research CouncilTIA: Therapeutic Innovation AustraliaWHO: World Health Organization

AHMAC: Australian Health Ministers Advisory CouncilANZCTR: Australian and New Zealand Clinical Trials RegistryCOAG: Council of Australian GovernmentsCPC: Clinical Principal CommitteeICMJE: International Committee of Medical Journal Editors

Funding

A fundamental feature of the ANZCTR policy context is that registration of clinical trials on ANZCTR is voluntary – there is no statutory requirement for clinical trial registration in Australia. That said, the case for registration of clinical trials is strengthened by a range of incentives. Foremost among these is that a prerequisite for publication in any of the ICMJE (International Committee of Medical Journal Editors) partner journals is clinical trial registration on a publicly accessible register before enrolment of the first participant. Other reasons put forward to support the case for clinical trial registration include:

Conformance to the Declaration of Helsinki;

Researchers’ responsibilities under 2007 Australian Code for the Responsible Conduct of Research;

Alignment with the National Statement on Ethical Conduct in Human Research 2007 (updated May 2015) which requires prospective registration; and

For NHMRC funded trials, the requirement for institutions to attest to compliance with the National Statement and Australian code for the responsible conduct of research.

The ANZCTR currently receives funding from the Australian Government’s Department of Health and the Department of Education and Training via Therapeutic Innovation Australia as part of the National Innovation Science Agenda.

As shown in the Figure 4-8 above, there are data sharing links between ANZCTR and other sites. Specifically, the ANZCTR is the primary data source for clinical trial information displayed on the Australian Clinical Trials website (www.australianclinicaltrials.gov.au)

30

http://www.australianclinicaltrials.gov.au/



managed by the Australian government and the Australian Cancer Trials website (www.australiancancertrials.gov.au) managed by Cancer Australia. Data from the registry is also supplied to a number of other independent registers on specific disease areas.

Data from the ANZCTR is used to identify clinical trials for the ClinTrial Refer app which seeks to promote patient recruitment and information sharing for clinicians. The ANZCTR also receives a live data feed from the US-based registry, ClinicalTrials.gov. The ANZCTR provides a weekly data feed to the WHO International Clinical Trials Registry Platform (ICTRP).

4.4 Current landscape

Aside from the ANZCTR, there are two additional sources of clinical trial data in Australia:

Regulatory trial notification through the Therapeutic Goods Administration’s (TGA’s) Clinical Trial Notification scheme (CTN) or approval scheme (CTX); and

Jurisdictional ethics and research governance data, e.g. Clinical Trials Jurisdictional Working Group’s National Aggregate Statistics (NAS) report.27

The definition of clinical trials for the TGA and for NAS is slightly narrower in scope than for the ANZCTR.

The aim of the ANZCTR is to ensure comprehensive registration of all clinical trials activity in Australia. However, this objective is not fully met. Recent reviews have found that there is a proportion of clinical trials undertaken in Australia that are simply not registered at all. Without comprehensive trial registration it is not feasible to accurately monitor the level of clinical trial activity in Australia, undermining one of the ANZCTR’s core objectives.

Separate to the issue of non-registration of a proportion of trials, a substantial number of clinical trials undertaken in Australia are registered internationally, rather than on ANZCTR. Of those Australian clinical trials that are registered, the ANZCTR estimates that it accounts for approximately 60%, ClinicalTrials.gov (the US-based clinical trials registry) for 35% and other WHO primary registries the remaining 5%. A very small proportion (1%) of clinical trials are registered on both the ANZCTR and ClinicalTrials.gov.

4.5 Expectations on reporting and compliance

There is an increasing focus from the research community on transparency and comprehensiveness of clinical trial registration. Despite this, audits of data compliance with WHO registry requirements from the ICTRP database have identified many trials with missing data in key variables including details of intervention specifics in drug trials and lags in trial registration after first participant recruitment. Compared to other international registries, a 2009 audit found that ANZCTR was one of three clinical trial registries that consistently maintains an extremely high data quality standard.

27 The NAS report is based on data from ethics and site assessment applications for clinical trials undertaken in public health services. To date, five jurisdictions have reported to NAS: ACT, NSW, Queensland, South Australia and Victoria, with NT contributing some clinical trial information to NAS.

31

http://www.australiancancertrials.gov.au/



A more recent (2018) review of the timeliness of registration on ANZCTR found that whilst registration lags still occurred for many trials, there had been improvement over time in the proportion of trials registered prospectively, from 48% in 2006 to 63% in 2012.

A number of reviews have canvassed stakeholders’ views on the accuracy of information reported to the ANZCTR. A strong critique is that the ANZCTR registry lacks currency. This limits the usefulness of the registry to provide up to date information on which trials are open and closed and the recruitment status. In turn, this has been reported to diminish the registry’s effectiveness in recruitment of patients and facilitating collaboration between researchers.

In the UK, the Health Research Authority has sought to promote more proactive and consistent prospective registration of clinical trials. A new rule was introduced in September 2013 in which ethics committees require trial registration no later than 6 weeks after recruitment of the first participant into a trial as a condition of Research Ethics Committee approval. A subsequent 2015 audit found that in spite of this formal requirement, only 55% of clinical trials approved by an ethics committee were included on a publicly accessible registry.

TrialsTracker gives users a live look at whether individual sponsors and trialists are meeting their responsibility to report the results of clinical trials on ClinicalTrials.gov. TrialsTracker shows that:

45.2% of trials conducted by major sponsors during the last decade are missing results; and

Since January 2006, major trial sponsors completed 25,927 eligible trials and have not published results for 11,714 of them.28

TrialsTracker is automatically updated when new information is added to the clinical trial register ClinicalTrials.gov. TrialsTracker was developed by academics at the University of Oxford. These researchers have estimated that 8.7 million patients were enrolled in the 11,714 trials identified by the tracker as missing results.29

4.6 Other jurisdictional approaches

Approaches to clinical trial registration in the US, Europe and UK are summarised below:

US – The ClinicalTrials.gov trial registry was launched in the US more than a decade ago and contains information on more than 100,000 clinical studies. There is mandatory registration for clinical trials covered by the Food and Drug Administration Amendments Act (FDAAA). Whilst not a Primary Registry, it links to the ICTRP search portal. It is governed by the National Library of Medicine at the National Institutes of Health.

Europe – The EU Clinical Trials Register contains information on interventional clinical trials conducted in the European Union, or the European Economic Area which started after 1 May 2004. The EU clinical trials register has been a primary registry in the WHO's Registry Network since September 2011 and is a WHO Registry Network data provider

28 . AllTrials, 2014, Launch of new TrialsTracker, Retrieved March 26, 2018, from http://www.alltrials.net/news/trialstracker/29 . AllTrials, 2014, Launch of new TrialsTracker

32



UK – Whilst there is no single primary registry in the United Kingdom, the UK Clinical Trials Gateway compiles information about clinical trials from several different UK registers. ISRCTN is a WHO primary registry with a registered office in London. Self-described as a ‘preferred partner’ of the UK Department of Health, the registry also registers trials outside the UK. It operates as a company limited by guarantee, is managed by a four-member board of directors and an advisory board with international representation.

Table 4-1 summarises key attributes of the abovementioned clinical trials registries.

33



Table 4-8: Key attributes of clinical trial registries

Attributes of registry ANZCTR ClinicalTrial.gov European Clinical

Trial Register ISRCTN

Jurisdictions covered

Australia and New Zealand

US -based with international registration

European Economic Area

UK-based with international registration

WHO Primary Registry

Primary registry Not a primary registry

ICTRP Search Portal links to

ClinicalTrials.Gov

Primary registry Primary registry

Governance & Organisational

Affiliation

Governed by Advisory Committee.

Organisational affiliation with

NHMRC Clinical Trials Centre,

University of Sydney

Governed by US National Library of

Medicine at the National Institutes of

Health

Governed by European Medicines Agency, European

Union

Governed by a four-member board of

directors.

Operational management by

BioMed Central Ltd editorial team.

Types of Clinical Trials

Interventional + observational


Not observational studies of medicines; Not trials of surgical procedures, medical

devices or psychotherapeutic

procedures


Cost to Register Free Free Free Charge of £ 226 to register

Statutory Requirements

Nil FDAAA European Union Clinical Trials

Directive

FDAAA

European Union Clinical Trials

Directive

Inclusion of Results

No Yes

Requirement of trials covered by FDAAA and for NIH-funded

clinical trials

Yes

Provision for summary datasets to be

included on registry.

Yes

Basic results in a scientific format.

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4.7 Forefront and future

Key issues of relevance to the future development of the ANZCTR are interoperability and data sharing.

Interoperability – Interoperability describes the extent to which systems and devices can exchange data and interpret that shared data. For two systems to be interoperable, they must be able to exchange data and subsequently present that data such that it can be understood by a user. Two third party systems that involve interoperable systems and which may have potential to streamline reporting to provide a ‘one stop shop’ relevant to clinical trials are: FHIR;30 and ResearchGate.

Data sharing – Building on the recent trends towards results of clinical trials being reported to registries, a further development in this direction is the sharing of individual participant data. This is premised on further promoting research transparency by enabling third party researchers to apply protocols to re-test results and explore alternative analytical concepts and research questions. In the ICTRP’s 2017 Joint statement on public disclosure of results from clinical trials, the benefits of sharing individual participants’ data and the facilitation of research through greater access to primary dataset were explicitly endorsed.

This ‘new frontier’ in trial transparency has been described schematically through a three-level hierarchy as shown in Figure 4-9. The apex of the reporting hierarchy would yield individual participant data (IPD) to enable re-analyses of trial data.31

Figure 4-9: New frontier of transparency in clinical trial reporting systems

30 . FHIR refers to Fast Healthcare Interoperability Resources31 . Zarin DA, ‘Participant-level data and the new frontier in trial transparency’, NEJM, 2013, 369(5):468-9

35



4.8 Summary

The ANZCTR’s key purpose is to provide comprehensive registration of clinical trials to promote transparency of clinical research, strategic targeting of research and to facilitate patient recruitment. A wide range of stakeholders have an interest in the registry and the policy context influencing the registry is complex. The role and purpose of the registry is directly influenced by the WHO, which accredits the ANZCTR as a Primary Registry. State and Territory governments and the Australian Government all have policy interests relevant to the registry. There is also a diversity of stakeholders who use the registry, directly or indirectly, including industry, researchers, health services and consumers.

The voluntary basis of trial registration in Australia contributes to one of the identified limitations of the registry – its lack of comprehensive coverage of all trials. A further reported shortcoming is data accuracy, particularly in relation to currency of data.

There are future opportunities for enhancing the role of the registry, influenced by a continuing trend for strengthening the transparency of clinical research. Registries in other jurisdictions have already adopted the reporting of results as a core requirement of registration – this is yet to occur for the ANZCTR. The next boundary being pushed, again in the interest of research transparency, is the sharing of individual participant data. This stage has yet to be implemented internationally.

Within the Australian context, recent innovations have occurred outside the domain of the ANZCTR. These include the use of apps for patient recruitment and the development of an integrated data-set (NAS) to generate performance metrics on key indicators including timelines for ethics committee approval and site authorisation. Of relevance to the ANZCTR, some observers of the Australian context have raised the prospect of streamlining the range of data reporting requirements to reduce reporting burden and achieve the registry’s integration within a ‘one-stop shop’ to support clinical trial reporting and governance.

36



5 Stakeholder themes

5.1 Scope of consultations

To support the consultation process, a discussion guide was prepared which outlined the purpose and context for the review. A copy of the discussion guide is provided as Appendix 1. It canvassed a range of questions under the following three main themes:

The appropriateness of the ANZCTR in addressing the current needs of all key stakeholders;

The efficiency of the ANZCTR in capturing a specified range of research activities, maximising the quality and completion of information, and minimising the burden to all stakeholders who utilise or otherwise manage the registry; and

The effectiveness of the ANZCTR as a current and future register of research activities, a source of accessible information to the public, and a comprehensive source of data for researchers, government and other key stakeholders.

There were 33 stakeholder consultations involving over 65 people, with representatives from the Australian Government, States and Territories, New Zealand, peak industry bodies, clinical trials networks, research institutes, universities, researchers and consumers. Eighteen meetings were face to face and the remainder by teleconference. The consultations predominantly occurred over the period 14 March to 16 April 2018. A complete list of the groups and individuals who participated in these meetings is provided as Appendix 2.

Additionally, a workshop was held with the Clinical Trials Project Reference Group on 1 May 2018 and with the Clinical Trials Collaborative Forum on 2 May 2018 with over 30 participants.

This report presents a thematic summary of these stakeholder consultations. It has been structured around the following topics covered in the consultations:

Role of the ANZCTR;

Functionality;

Data integrity;

Areas for enhancement;

Alternatives to ANZCTR; and

Innovations of relevance to ANZCTR.

37



5.2 Role

A key question of relevance to this review concerns clarity of role and purpose. All stakeholders were asked to provide feedback on what they considered to be the main role(s) currently served by the ANZCTR.

What do you consider to be the main role of the ANZCTR?

ANZCTR has a very clear articulation of its current role and purpose. The ANZCTR sets out the following key objectives:

Promote transparency and reduce the risk of publication bias and selective reporting;

Promote awareness of the range of clinical trials which are recruiting to facilitate recruitment for researchers and potential participants;

Build awareness of similar or identical trials, limiting the likelihood that research is duplicated;

Determine gaps in clinical trials research by enabling access to information on trials;

Enhance the quality of clinical trials through data checking at the point of trial registration; and

To promote research collaboration.

Most stakeholders mentioned at least the first three of these objectives as summarised below:

To improve research transparency: Making details of all trials publicly available improves research transparency and helps to overcome publication bias and selective reporting, thereby enabling clinicians and consumers to make more informed decisions.

“It’s essential that we have a registry, to record all the trials being conducted to prevent publication bias.”

To avoid duplication: Improving awareness of similar or identical trials will make it possible for researchers and funding agencies to avoid unnecessary duplication.

“The ANZCTR should be the curator of correct information (to avoid duplication).”

“Value for Money in research and lack of duplication is really important.”

To facilitate trial participation: People interested in participating in a clinical trial and clinicians investigating relevant trials for their patients have access to a reputable and comprehensive on-line register showing what trials are occurring across all areas of health, which may facilitate recruitment.

“It’s an information resource and when used correctly, can provide an avenue to connect with patients.”

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“Provides a point of reference for patients, as well as recruitment.”

“As the patient/doctor relationship changes over time, so should the ANZCTR – it will move over to more of the recruitment aspect. Patients are more likely to search now, as opposed

to seek information from doctors.”

Not all stakeholders considered the registry’s role was to promote patient recruitment.

“The purpose of the registry is not to enable recruitment. Rather, to ensure research transparency and trust.”

“Recruitment is only a requirement if the purpose of ANZCTR changes and so does the target audience.”

“As a recruitment resource? It's broken.”

In addition, these roles for the registry were identified by some stakeholders:

To identify potential research areas: Describing clinical trials in progress can make it easier to identify gaps in clinical trials research.

“It can be used for broader purposes, such as understanding what research is being conducted especially in Australia and New Zealand. In particular, understanding what may

not have been published.”

“Registries are critical because they enable researchers to scan the landscape and identify the state of the research effort already into trials in a particular area. If there is research

focused on areas previously researched, it can leverage off previous trials including replicating research design and purposeful use of protocols. Such a strategic, systems

stance will involve collaboration and will ensure clinical trials are well planned in advance so that there is adequate statistical planning, budget planning and governance to ensure

CTs are able to succeed with patient recruitment and achieve research milestones. In turn this delivers value for money to Australia.”

To improve trial quality: Registries checking data as part of the registration process may lead to improvements in the quality of clinical trials by making it possible to identify potential problems (such as problematic randomisation methods) early in the research process.

“The more researchers use the registry first for systematic reviews, the more likely protocol differences will be picked up.”

To promote research collaboration: Enabling researchers and health care practitioners to identify trials in which they may have an interest could result in more effective collaboration among researchers.

“As a researcher the principal purpose is that it serves as a gateway to publication, but can provide a more efficient way for smaller networks of researchers to connect.”

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To promote evidence-informed decision making: Registries enable details of clinical trials to be communicated widely and there is an increasing trend for systematic reviews to be based on searches of clinical trial registries, in addition to reviews of published studies. This becomes more relevant with international trends for research protocols and results being incorporated on registries.

“Clinical Trial Registries are a big part of the jigsaw piece, and if done correctly, it will be the source of truth – the journal article will just become a nice advertisement for the trial and if you want more information, then head

to the registry.”

To promote accountability for quality research and outcomes: This is linked to the broader focus by the NHMRC to lift the planning and rigor of clinical trials to ensure the research plans are feasible and that targets for recruitment are realistic. Such a strategic, systems stance must involve collaboration and ensure clinical trials are well planned in advance so that there is adequate statistical planning, budget planning and governance to ensure clinical trials are able to succeed with patient recruitment and achieve research milestones. In turn this is perceived to be the basis to deliver value for money to Australia.

“Accountability for trial design is important. What you aim for at the outset is what is upheld in the approach to the clinical trial.”

How do you use ANZCTR?

Whilst there was general agreement that an Australian clinical trials registry was an important and necessary tool, most interviewees did not use the ANZCTR often in their day to day work life.

“I don’t use it massively, only to register clinical trials”.

Typically, those who are mainly involved in international clinical trials tend not to use ANZCTR regularly, opting instead to use ClinicalTrials.gov.

Some clinicians stated that there are nomenclature differences between research medicine and clinical practice and for this reason it would be unlikely that most clinicians would routinely turn to the registry as an information resource.

“I tend to use it as a last resort. There are nomenclature differences between research medicine and clinical practice.”

“Researchers would use many other search engines before using the registry”.

Some responded that the ANZCTR provides them with an excellent “starting point and point of reference and citation” before obtaining the “rest of the picture” from other resources.

Very few representatives from government departments tend to routinely use the ANZCTR.

“We don’t really use it, even from a policy perspective”.

Most agree that there is limited reliance by consumers on the registry and that for most consumers it would be too challenging to navigate the website. For those consumers

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seeking to participate in a clinical trial, most considered that the current registry is likely to be too confusing and especially in relation to obtaining clear information on which trials are open, whether a patient meets eligibility criteria for a clinical trial, and the location of trial sites.

A consumer commented that relative to ClinicalTrials.gov, ANZCTR was less user friendly.

“Compared to ClinicalTrials.gov, ANZCTR was much more difficult as it appeared to be tailored for researchers. The advantage of CinicalTirials.gov is that Inclusions/exclusions are visible.”

Another consumer commented that the headings (or Titles) and Descriptions for most trials are not easily understood by the average patient.

“Often written in awkward & technical language that has to be read several times to try to understand. The Victorian Cancer Trials website provides a 'patient-friendly' version of the Title and basic info for each trial to

make it easier for us.”

“It’s time to look at how we provide better and more accessible information about clinical trials here in Australia. It needs to be done in ways that encourage patients and their family/carers to engage – to look up trials, to get to

understand the concepts eg re Phases etc, or even just to not be afraid of the idea of being in a clinical trial.”

Many other stakeholders reiterated the point that the ANZCTR was considered difficult to navigate for consumers.

“Information provided, isn’t really user friendly, and in lay person terms.”

“It’s hard to navigate, even for someone who has clinical trial knowledge. Hard to drill down into great detail. Needs to make it more user/consumer friendly.”

“It's not set out in a lay way. You’ve got to have an understanding of clinical trials to know what you're looking for. We prefer using ClinicalTrials.gov. The information is laid out a little bit clearer. There are two obvious

portals... a researcher using it versus patient.”

5.3 Functionality

ANZCTR states their users, and therefore stakeholders, are registrants, researchers, consumers, and clinicians. However, many stakeholders responded that with this extensive list of users they are “trying to be all things to all people”, and that is “the root of their problem” in seeking to be both more accessible and also functional.

Many reported that they found that the ANZCTR is not as easy to use as it could be.

“ANZCTR is somewhat functional but not terribly accessible in its current state” “It isn’t very user friendly and it is hard to find anything that you are looking for. An issue for improvement that ANZCTR should look at, is its link-ability to other sites and information, and it’s searchability – how

quickly can someone find information within ANZCTR.”

Most stakeholders considered that the search engine could be more user friendly.

“It is quite difficult to find a trial through the search function, if you have the record number it is fine, otherwise it’s really difficult to navigate and search”

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There were instances of stakeholders who stated that once they had managed to find the trial (through the record number), they found that the terms they were searching are within that record. Despite this, they reported that they could not find the record initially.

“We recently attempted to use ANZCTR but had to move to data modelling because [the registry’s] data wasn’t as interrogable or easily searchable”

5.4 Data Integrity

Stakeholders have varied opinions on ANZCTR’s data integrity.

“ANZCTR do a great job for being an up to date registry”

“Once found, the information is of high quality and detail. The only issue with the level of detail is it isn’t granular enough at a trial level (sites, results etc.)”

“ANZCTR is not current - a trial can stay on the registry’s site, not updated, for years”

Some stakeholders believe this lack of data currency is inevitable.

“There are always some delays with information (4-6 months in some instances) as it is generally the last place researchers think about updating”

Many pointed out that sponsors and funders should be best placed to improve this problem.

“The funders are the ones with the power to improve ANZCTR, they could insist that funding won’t be released until the record is updated or completed”

A few stakeholders have positively referenced, in terms of data integrity, the TGA approach which has traceability expectations and believe there should be the same expectations for the ANZCTR.

“We would love to use ANZCTR however, the registry’s accuracy is the reason it's not used, for example the status of a trial.”

Most stakeholders believe that resolving issues around data integrity is a crucial step for the ANZCTR.

“Unfortunately, ANZCTR in its current state is not capable of being world class again, and at the crux of it is data integrity”.

5.5 Enhancements

Unsurprisingly, the most obvious enhancement raised by stakeholders was in relation to improving data integrity. When asked for a potential solution, many advocated the application of sanctions to both enforce use of the ANZCTR and also to ensure regular and timely updates.

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“Government should mandate the registration of clinical trials being undertaken in Australia, or provide a formal tick that ANZCTR is the one stop shop for clinical trials in Australia”

Patient recruitment

Many stakeholders agree that patient recruitment is a key role for the ANZCTR, however most considered that it currently is not fulfilling this role.

““Patient recruitment should have been one of its roles. And should be one of its roles in the future, it's just not doing it well. Currency and accuracy - and location data - and the concept of small

networks...these have a role in increasing recruitment.”

“Geocoding to improve patient recruitment. And enough information on inclusion/exclusion criteria for clients to know if they're applicable.”

Some considered that ANZCTR should play an enabling role in relation to patient recruitment. That is, that it should be the source of trusted data that is searchable by patient recruitment apps – but the ANZCTR should not to take on an app development role directly.

“ANZCTR should split the function [of patient recruitment] and use a different portal or have a phone app, soon ClinTrialRefer are working towards having a linkage with ANZCTR, with a way to streamline data entry into the

app.”

“The registry should be able to be searched from other organisations, such as Google, or the ClinTrialRefer App… however ANZCTR shouldn’t be responsible for this, rather other

companies can do that.”

“ANZCTR should be used as a database, and then third party apps to connect into that database.”

“Patient recruitment could be boosted if rather than have a passive website, it gets shown and linked to more common sites such as Health Engine, Facebook.”

Results

Many stakeholders agreed that trial results should be included within the ANZCTR.

“It is something that is absolutely relevant and really needed”.

“It is the next logical step”

“Results should be published for transparency and knowledge and research integrity”.

“Registries will become the repository for all results, and furthermore begin storing and reporting protocols”

Some take it further and believe that the publication of results provides an avenue to ‘close the feedback loop’, providing a method to check the trials that do not have results and provide them with a notification. Publishing results can play a crucial role in fostering research transparency.

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“By requiring results to be published, we can hopefully stop scenarios where a product looks promising, but it becomes obvious that it is toxic, the company goes bankrupt and there is no one left in the company to take

accountability”

Performance metrics

Some consider that the inclusion of performance metrics is a logical extension of the registry's role. This would overcome the issue that NAS has limited coverage to public health services. It would promote accountability of the sector and link to the broader government policies on improving competitiveness of the sector.

“There are two metrics that are essential for measuring clinical trial recruitment: Metric 1: First patient in (time between start to first patient) – needs to be a max of 40 days; Metric 2: Did you recruit to target? The MRFF is

going to be funding a lot more in clinical trials, and they will want return on investment these outcome measures”

“Could include performance metrics on time to start, recruitment, proposed end date, publication, completion of recruitment, and cross reference to final study report.”

“Metrics on ANZCTR itself, such as number of records actively updating, or number of trials that lead to publication, would be great.”

“An area of ongoing concern for industry sponsors in Australia are the long timelines of ethics approvals and the high costs of setting up and running clinical trials at healthcare facilities. Transparency in this area would enable

to identify high performing sites and provide an incentive for low performing sites to improve.”

“We would love extra metrics, but ONLY if it can obtain the information from the already current sources.”

“The management and ongoing operations of the ANZCTR should be transparent, for example through annual reporting on performance KPIs and cost of administering the ANZCTR. Stakeholders – representatives of

industry, healthcare professionals and patient groups – should have a say in establishing of the KPIs.”

Others consider that ANZCTR should not extend its remit. Rather, the focus should be only on capturing the registry data fields relevant to WHO and ensuring that this role is accurate and current. These stakeholders believed that NAS is effectively covering off the issues around performance metrics and there is scope to extend this.

“Not sure that the registry is the right place to do that. Governments are keen to promote Australia as the place to do clinical trials and effective and high-quality research. The jurisdictions and health authorities should be

where these metrics should be developed.”

Interoperability

Another enhancement, the ANZCTR has intended to consider, is making its system more interoperable, providing further linkages, with other systems operating within Australia. These include linkages to other jurisdictional research and governance systems (such as HREA from HRECs), to the online CTN systems at the TGA, and the ability to source and include data from Australian trials registered on all the WHO Primary Registries.

Many would like to see it become a part of a one-stop shop pipeline for trials, extending its coverage to items such as regular reporting, tracking clinical trial trends and their subsequent policy impacts, providing policy initiatives to improve clinical trials research,

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providing links for recruitment, ethics application process, research governance and grant applications.

“It is necessary to have one place to track everything for clinical trials, a holistic approach to clinical trials in Australia.”

“A link to ethics and ANZCTR to help close the loop and improve the currency of ANZCTR.”

“Better integration with these other systems (i.e. HREC) would be useful.”

“There is logic for a nationally consistent approach to monitoring clinical trials research given that the main game is to build the competitiveness of Australia relative to other global players. This is more important that

jurisdictional competition.”

Conversely, others considered that ANZCTR should stay with its initial purpose as a vehicle to provide transparency and reduce research duplication while promoting collaboration.

“Bringing metrics, such as NAS, into the ANZCTR just creates duplication.”

Risks

Stakeholders agree that while it would be very useful if information such as, NAS, accrual rates, and adverse event reporting were included in ANZCTR, they understand that such an upgrade would be expensive to implement and maintain.

“The more functionality you add in, the more resources required.”

Others point to being flexible and adaptable as a key driver for the ANZCTR in the future and thus adding many features can make the registry cumbersome.

“Becoming interoperable has the inherit risk of becoming rigid in our data requirements – a uniform standard makes it too stuck.”

5.6 ClinicalTrials.gov

The ClinicalTrials.gov trial registry was launched more than a decade ago. Since that time, it has been evolving in response to various policy initiatives. The registry now contains information on more than 100,000 clinical studies and has emerged as a key element of many public health policy initiatives aimed at improving the clinical research enterprise.

It has been noted by researchers and commercial stakeholders that moving from ANZCTR to solely relying on ClinicalTrials.gov is a possibility as many international studies already use ClinicalTrials.gov.

“Using only ClinicalTrials.gov is a potential option and provides a single source of truth. However, if we want to use the registry for recruitment then we need to use a local registry.”

“Using ClinicalTrials.gov can “reduce global duplication and provide a single site and resource – a behemoth registry.”

“It is pointless having a ClinicalTrials.gov shadow”

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Conversely, the majority of stakeholders believe it is not a viable option and will lead to Australia being reliant on a registry not attuned to the local landscape.

“It is important that Australia has its own clinical trials registry resource”

“Using ClinicalTrials.gov is not ideal, as the USA has much different terminology, and their processes and policies are vastly different”

“It reduces the flexibility to adapt and change to the needs to Australia”

“If registration is just a hurdle requirement for publishing, then, ClinicalTrials.gov would be perfectly fine, but if the registry is about being more focused on a comprehensive picture of research in Australia and communicating

with patients and researchers then a local, independent registry is the way to go.”

Others point to the volatility of the American political and funding context, highlighting reduced budgetary allocations to NIH as a case in point of the risks entailed in divestment.

“ClinicalTrials.gov is even worse, and the same problems would still exist.”

5.7 Other Innovations

When asked to think ‘outside the box’ for potential future innovations for the ANZCTR, many spoke about linking the ANZCTR into Australia’s healthcare infrastructure and systems. Examples of more proactive approaches to patient recruitment at a future point would be to allow linkages to MyHealth records to find people suitable for trials.

“People are crying out for data matching – that is match trial criteria against electronic medical records. Unfortunately, ANZCTR’s data accuracy and currency is stopping this.”

Another suggestion was to provide distinct avenues for patient recruitment, with ideas such as utilising user accounts and providing links with social media, providing ANZCTR, and clinical trials in general.

“ANZCTR has the potential to promote and enhance discussion about clinical trials within Australia if done correctly”

“Recruit both participants and healthy controls and improve ANZCTR to go beyond being just a registry - providing links to tissue and blood banks”.

“We have a valuable opportunity to turn this into a tool with clear value added for the Australian population, and it would be a big mistake and missed opportunity to not provide more.”

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6 Strategic response

Based on the review of ANZCTR’s role in the context of WHO requirements, best practice developments in other jurisdictions, feedback from stakeholder consultations and workshops with the sector, it is apparent that there are several issues confronting the ANZCTR. These have been encapsulated into five broad themes or ‘problems’:

The registry has incomplete coverage and inconsistent data quality;

The registry is not easy to use;

Trial results are not reported to the registry;

There is a lack of integrated performance metrics and system inter-operability; and

The registry lacks strategic governance.

Key benefits that would flow from addressing these problems include:

Improved research transparency;

Avoided duplication of research;

Improved patient recruitment;

Improved sector efficiency and value for money; and

Improved accountability of the registry.

Importantly, the first three of these benefits are consistent with the current role and purpose of the registry. The last two benefits are new priorities for future development.

Figure 6-1 shows schematically that the achievement of these benefits relies upon a range of strategic responses.

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Figure 6-10: Investment logic map

Incomplete coverage &

inconsistent quality

Not easy to use

Results are not reported

Lack of integrated performance

metrics

Lack of strategic governance

Research transparency

Improve patient recruitment

Improve sector efficiency & value

for money

Improve accountability

Problem Benefit Strategic response

Improve registry coverage & data

quality

Improve IT search & navigation functions

Enable results to be reported

‘One-stop shop’ with KPIs & streamlined

reporting

Strengthen governance

Avoid duplication of research

6.1.1 STRATEGIC RESPONSES

Each of the five strategic responses and recommended changes is described below.

Strategic response 1. Improve registry coverage and data quality Increase coverage – The ANZCTR does not currently provide comprehensive coverage

of all clinical trials undertaken in Australia, detracting from the registry’s core goal of promoting transparency of all research. This lack of full coverage limits the capacity of government and industry to have an accurate assessment of activity and investment in the sector.

An important provision of the National Statement on Ethical Conduct in Human Research (2007, updated July 2018) (National Statement) concerns the role of researchers in registering trials on a publicly accessible registry. Under the July 2018 update, clause 3.1.7 has been strengthened and requires that researchers ‘must’ register a clinical trial in advance of patient first recruitment (previously the wording was ‘should’). It will be important to ensure that these strengthened provisions in the National Statement are reflected in increased rates of timely trial registration. (A separate consideration, addressed below in relation to ‘currency’, is whether the registry is kept up to date and whether such a provision should be included in the National Statement.)

Recommended change:

Develop tighter reconciliation processes of clinical trials approved by ethics committees with trials registered on ANZCTR, ClinicalTrials.Gov or other primary

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registries and develop exception reports to identify instances where clinical trials approved by ethics committees have not been registered.

Currently there is a weekly feed to the ANZCTR of clinical trials being undertaken in Australia that are registered on ClinicalTrials.gov. Other registries which have sizeable numbers of Australian trials registered are: ISRCTN.org; German CTR; and EU-CTR.

Recommended change:

Include regular data feeds to the ANZCTR of Australian trials registered on ISRCTN.org; German CTR; and EU-CTR.

Improve currency - Most stakeholders considered that the biggest shortcoming of the registry was the lack of currency of trial data. There are two elements to currency:

The relative proportion of trials that are prospectively registered prior to trial commencement (~65-70% of trials are prospectively registered on ANZCTR); and

The proportion of trials that are updated annually (currently 55% to 60% of trials).

The ANZCTR’s Standard Operating Procedures (SOPs) include a provision for email notifications to be sent to registrants with reminder notifications to update the trial registry record at 11 months following registration or the most recent update.32 Depending on the response of the registrant, the registry record is subsequently flagged publicly as “Up to date” or “Not up to date” (excepting records flagged as completed, terminated or withdrawn).

Recommended changes:

Revise the National Statement to include a provision for ethics committees to require trial coordinating principal investigators to provide evidence that a trial registry is up-to-date as part of the 12 monthly ethics committee review process;

Implement targeted, repeat email notifications at 48 weeks, 50 weeks and 51 weeks with SMS and phone follow-up at week 50, to increase the proportion of trials updated annually;

Implement audits to identify characteristics out of date records; and

Implement KPIs for currency that include targets for annual improvement (75% of records up to date in year 1, 85% in year 2 and 90% in year 3) and make these (de-identified) results publicly available in aggregate and trial categories (jurisdiction, sponsor type, and industry type).

Strategic response 2: Enable results and protocols to be reported Inclusion of results – A recent development in the US and the UK has been the

requirement for summaries of clinical trial results to be reported to clinical trial registries. This is consistent with the fundamental aim of increasing research transparency. The inclusion of results is one of the proposed optional data fields identified in the ICTRP’s International Standards for Clinical Trial Registries. Currently, the ANZCTR has a field for reporting of website links to publications but does not have a facility to report actual clinical trial results.

Recommended change:

32 ANZCTR, 2017, Standard Operating Procedures, p. 91

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Develop IT enhancements to allow for results of clinical trials to be reported to the ANZCTR and, after appropriate acceptance testing, make this a mandatory field.

Inclusion of protocols – Inclusion of protocols is another development that seeks to promote transparency and facilitate reproducibility of methods. ANZCTR has been undertaking research in collaboration with Canada to explore the implementation of SEPTRE for inclusion in the ANZCTR. This facility already exists within ClinicalTrials.gov.

It should be noted that for some trials, protocols may not be able to be published in full and at the commencement of the trial due to the commercial-in-confidence information contained within.

Recommended change:

Review the feasibility of adopting standards for electronic protocol reporting (SEPTRE) for inclusion of protocols on the ANZCTR and after appropriate acceptance testing, include this as a mandatory field for the ANZCTR for publicly funded trials in the first instance.

Strategic response 3: Improve IT search and navigation functions Improve functionality – Stakeholder feedback indicates that the search functionality of the

current registry is less than optimal.

Recommended change:

Upgrade search capabilities by implementing fuzzy logic and phonetic searching.

Add geo-coding – One of the key roles of the ANZCTR, consistent with the WHO expectations of a Primary Registry, is to facilitate patient recruitment. Stakeholders consider there are insufficient details available about the location of trial sites and contact details of trial principal investigators.

ANZCTR has some provision currently to include site details. The enhancement that is required is to enable ease of search for trial sites by geographic search terms.


Include geo-coding details in search fields in ANZCTR to enable users to search for trials by geographic search terms such as state, suburb or postcode;

Include contact details of Australian principal investigators for trials that may be registered on ClinicalTrials.gov by including these trials on ANZCTR through a secondary registration process and include details of Australian trial sites on ANZCTR.

Strategic response 4. Develop or become part of a one-stop shop with KPIs & streamlined reporting

This strategic response involves a broadening of the role of the registry.

Integrated performance metrics – For a subset of clinical trials undertaken in Australia – those undertaken in public health services in five National Mutual Acceptance (NMA)

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participating jurisdictions and from the Northern Territory33 – there are metrics provided through NAS that provide important performance information about clinical trial study start-up timelines. NAS reflects the agreed (with industry) minimum data to measure the performance of the clinical trials sector and to drive process improvements. These include timeliness from ethics application submission closing date to date of first site authorisation.

The data that underpin these performance metrics are sourced from the research governance information systems (AU RED, REGIS, ERM) operated by five jurisdictions New South Wales, including ACT, Victoria, South Australia and Queensland.34 There is a planned expansion of NAS and all jurisdictions are working towards this. In the next reporting period (2017/18), all jurisdictions (except Tasmania) are expected to provide NAS data, and the CTPRG is also working with the private sector to investigate options for NAS equivalent data.

Streamlined reporting – Currently there is a substantial reporting burden faced by researchers involved in clinical trials. Aside from ANZCTR trial registry reporting requirements there are reporting requirements to HRECs, and depending on the trial, to the NHMRC’s RGMS35 and the TGA’s CTN data-bases. There is no interoperability between these data-bases currently leading to a requirement for multiple reporting.

Recommended change:

Develop IT interoperability enhancements to enable performance metrics currently reported to NAS to be incorporated within ANZCTR or a one-stop shop and review the feasibility for streamlined data feeds between ANZCTR and other systems including TGA’s CTN data-base and NHMRC’s RGMS;

Concierge support – ANZCTR currently provides support to queries from registrants at the time of trial registration and when updates are required. To improve the efficiency of the registration process, ANZCTR introduced automation and logic rules in 2015.

These efficiency initiatives are supported. However, it is apparent that despite these initiatives and automated update notifications, there are continuing issues with the currency of data reported to ANZCTR. There is a need for a concerted, proactive engagement with trial registrants to maximise ease of trial registration and trial updates to ensure currency. This will be particularly important to support additional initiatives such as the introduction of results and protocol reporting to the registry.

Recommended change:

Redevelop the ANZCTR hotline with a dedicated concierge function to support investigators inputting information, to support consumers seeking information about access to research trials and to maximise the currency of the registry.

Strategic response 5: Strengthen governance

33 Clinical Trials Jurisdictional Working Group 2016, Framework for National Aggregate Statistics (NAS), Second Activity Report on Clinical Trials in Australia Public Health Institutions: Canberra, p. 7.34 As an alternative to AU RED, next generation research governance information systems are being implemented in several jurisdictions including RGS (Western Australia), REGIS (NSW and ACT) and ERM (Victoria and Queensland).35 NHMRC is replacing the existing Research Grants Management System (RGMS) with Sapphire, a new grants management solution

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Current governance is through an advisory committee that has a relatively low engagement with the registry, meeting only once per annum. The organisation lacks a strategic plan and business plan. The ANZCTR has undertaken many enhancements to the registry and actively contributed to the WHO’s endeavours and published widely. Despite this, there is insufficient outward engagement by the ANZCTR with its Australian and New Zealand stakeholders and its future strategic directions are unclear.


To enable implementation of the strategic responses outlined in this review, there is a requirement to revise the terms of reference and reconstitute the governance committee. A new Board of Management should be established with revised terms of reference that would include responsibility for:

(1) Implementation of the strategic directions arising from this review in accordance with a funding agreement with relevant government departments. The funding agreement would specify key change priorities, performance KPIs and resource commitments;

(2) Developing and implementing a strategic plan, operational business plan (inclusive of workforce and resourcing), stakeholder communications plan, strategic research plan and a performance management framework aligned with the funding agreement; and

(3) The Board of Management would have six members and would meet quarterly. Committee representation would be from government (two Commonwealth Government representatives and one State Government representative), from industry (one representative), research (one representative) and a consumer advocacy organisation (one representative). A group larger in size would be unwieldy and unsuited to the ‘fleet of foot’ agility required to drive the change agenda.

The Board of Management would have a time-limited appointment (three to four years) with defined milestones for implementation of the review recommendations.

To enable continued engagement with the breadth of stakeholders relevant to the ANZCTR’s enhanced role, a 10 to 12-member Reference Group would be constituted and would meet at least yearly, including as relevant New Zealand representation. The Reference Group would have an advisory role to the Board of Management. It is not assumed that the current Advisory Group membership would necessarily transfer to the new Reference Group.

Any future governance arrangements must be transparent and formalised with public annual reporting. Depending on the structure of the not-for-profit entity,36 public reporting (inclusive of governance and financial performance reporting) would need to comply with ACNC (Australian Charities and Not-for-Profit Commission) requirements.

6.1.2 DISINVESTMENT OPTION

36 WHO’s ICTRP standards require that Primary Registries be governed by a not-for-profit organisation.

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The option of disinvestment and reliance on ClinicalTrials.gov was considered. This option would effectively result in the cessation of the ANZCTR. There are three main arguments advanced for this option:

It is the simplest way to avoid duplication of entry of information about trials on registries;

Most industry-driven multi-site clinical trials already use ClinicalTrials.gov as the default registry; and

There are FDA mandates for registration on ClinicalTrials.gov for prospective approval in the US pharmaceuticals market. Reduces global duplication.

In discussions with stakeholders, several disadvantages were identified with such an option:

It would not be attuned to the local Australian context and would reduce the scope for promoting local participation in clinical trials through the inclusion of Australian site details;

ClinicalTrials.gov is limiting registration requests from other regions;

There would be no scope to develop the registry to promote integrated performance metrics of general relevance to the industry;

There would be no scope to adapt terminology and augment the registry data fields to meet Australian requirements; and

Australia would have no influence on the strategic direction of the registry nor on its governance. Australia would cede influence it currently has with the ICTRP and there would be a likely diminution of Australia’s standing within the WHO and more widely.

In addition to the disadvantages listed above, the disinvestment option would not achieve the benefits previously listed for strategic responses 1 to 5. For these reasons, the disinvestment option is not recommended.

Summary of options

Figure 6-2 summarises the strategic responses under four options:

Option 1 involves no change to the current role undertaken by the ANZCTR and would aim to:

Improve registry coverage, currency and data quality (strategic response 1);

Improve IT search and navigation functions (strategic response 3); and

Strengthen governance (strategic response 5).

Option 2 would involve a minor extension of the current role served by the ANZCTR and would aim to:

Enable results and protocols to be reported (strategic response 2); and


Option 3 would involve a major extension of the current role served by the ANZCTR and would aim to:

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Integrate the registry within a one-stop shop with KPIs and streamlined reporting (strategic response 4); and


Option 4 would involve a discontinuation of ANZCTR’s role:

Disinvestment option (not a recommended strategic response)

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Figure 6-11: Summary of options

1 May 20181

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Remove ANZCTR and rely solely on ClinicalTrials.gov

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Concierge supportStreamlinedreportingPerformance metrics (NAS)Include results Improve functionalityImprove currencyIncrease coverageAdd geo-coding

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Include results Improve functionalityImprove currencyIncrease coverageAdd geo-coding

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Improve functionalityImprove currencyIncrease coverageAdd geo-coding

Strengthen Governance

It is apparent that options 1 to 3 are sequential, with each building upon the preceding option. Underpinning options 1 through 3 is the common requirement for strengthened governance. The fourth option, disinvestment, is not a recommended strategic response.

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7 Implementation issues

This chapter presents key risks, mitigations and a proposed implementation timeframe.

7.1.1 RISKS

There are seven main risks involved in the implementation of the review recommendations. These are summarised below together with proposed mitigation options.

Value for money Risk:

There is a risk that a continuation of funding to the ANZCTR without undergoing a market-testing, contestable process, will not achieve value for money.

Mitigation:

Undertake a contestable tender process and commission a not-for-profit organisation with suitable expertise to undertake the operation of the registry and implement the strategic changes outlined in this review.

Operational continuity Risk:

There is a risk that continuity of the operations of the registry will be adversely affected through the commissioning process. This could further disengage stakeholders and reduce the relevance of the registry in achieving its key roles.

Mitigation:

An implementation plan needs to be developed to address the approach to the management of business-critical functions required to ensure day to day operation of the registry during the commissioning process.

A business continuity plan should be developed to enable core operational functions to be maintained throughout the commissioning process.

A transition in and transition out plan will need to be developed and implemented.

Stakeholder support Risk:

There is a risk that stakeholders may not support the strategic directions recommended from this review and that future strategies requiring inter-operability of the registry with other data-bases are not able to be implemented.

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Mitigation:

There has been considerable consultation with stakeholders in developing the recommendations. Feedback from stakeholders on the review recommendations should be sought and considered in the framing of an implementation plan.

Resource adequacy Risk:

There is a risk that the funding required to implement the changes outlined in this review are not available, limiting the extent and effectiveness of changes required.

There is a risk that the period of funding specified in the commissioning process is too short and that this limits the level of market interest in responding to a tender bid.

Mitigation:

Subject to usual government resourcing considerations, seek a three-year funding envelope in the first instance with a view to ongoing recurrent funding to enable funding certainty for the registry.

Establish and ‘quarantine’ the implementation funding required to implement the changes outlined in this review as a separate budget allocation to the recurrent funding required for ongoing operation of the registry.

Interdependencies Risk:

There is a risk that the interdependencies between strategic responses recommended in this review are not managed leading to partial benefit realisation. For example, a key interdependency for enhanced data quality is the implementation of further changes to the National Statement to require researchers to provide evidence of registry updates as part of 12 monthly HREC progress updates.

Mitigation:

A comprehensive implementation plan needs to be developed to identify interdependencies of each strategic change to achieve the required benefits.

Complexity Risk:

Option 3, (integration within a one-stop shop) results in the registry taking on additional roles and this role enhancement may create a risk of added complexity to the operational functioning of the registry.

There is a clear rationale for seeking interoperability between the ANZCTR and AU RED (and similar jurisdictional ethics committee governance data-bases such as ERM [Victoria and Queensland], REGIS [ACT, New South Wales] and RGS [Western Australia]). That is, enabling linkage between the clinical trial registry with

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research governance information systems is integral to the strategic objective of achieving high levels of data quality on the registry through promoting prospective registration of clinical trials and updating the clinical trial registry in alignment with ethics committee progress updates. Inclusion of performance metrics on the registry including timeliness of start-up times from ethics application to first patient recruitment is directly linked to the registry’s role of facilitating patient recruitment.

There may be additional benefits from achieving interoperability between the ANZCTR and the TGA’s CTN data-base and the NHMRC’s RGMS data-base. Benefits may include efficiencies through reduced reporting burden and potentially, enhancements to currency through inter-operability with these data-bases.

Mitigation:

To mitigate the risk that role enhancement add complexity and jeopardise operational performance, there is a requirement to have a staged approach to any planned inter-operability enhancements. Specifically, this requires further feasibility assessment of interoperability for each separate information system namely:

(1) ANZCTR and AU RED (and similar jurisdictional ethics committee governance data-bases such as REGIS, ERM and RGS);

(2) ANZCTR and NHRMC’s RGMS; and

(3) ANZCTR and TGA’s CTN data-base.

Innovation Risk: There is a risk that the service requirements for a registry with enhanced roles may

be overly prescriptive leading to a stifling of innovation in the delivery of solutions.

Mitigation:

To mitigate this risk there is a need to clearly specify the core roles and outputs to be delivered by the registry in any commissioning context and to seek innovative approaches to the delivery of current and new functions. Procurement strategies, particularly for IT solutions for inter-operability, should not be overly prescriptive and should align with currently available, compatible technologies using best practice development standards including but not limited to FHIR (Fast Healthcare Interoperability Resources).

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7.1.2 IMPLEMENTATION TIMEFRAME

Indicative implementation timeframes for each option are outlined in Figure 7-1.

Figure 7-12: Implementation timeframes by option

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Appendix 1 Stakeholder discussion guide

Context

Clinical trials are essential for evaluating the effectiveness and safety of drugs, devices, services and interventions to help prevent, detect or treat illness and disease. It is through the research done in clinical trials that people gain more timely access to better treatments.37 They are a fundamental driver of models of care and advancing the quality and safety of health care.

Economically, the breadth of clinical trials undertaken in Australia is substantial. Clinical trials are worth in the order of $1 billion to the Australian economy each year and serve as a key employer of Australia’s highly skilled workforce.38 Continued growth of clinical trials is largely dependent upon government policy, with recent additional investments from the National Innovation and Science Agenda and the Medical Research Future Fund.

Australia’s clinical trials environment is complex, with various responsibilities resting with institutions, private organisations and companies, State or Territory Governments and the Commonwealth Government. As there is no one government or entity that controls all the levers for clinical trials, the Clinical Trials Project Reference Group (CTPRG, formerly the Clinical Trials Jurisdictional Working Group) has been working since 2014 to ensure a nationally cohesive approach to enhancing the environment for clinical trials and improving Australia’s attractiveness as a place to conduct clinical trials.

ANZCTR

The Australian New Zealand Clinical Trial Registry (ANZCTR) is a critical component of national clinical trial infrastructure, and part of a worldwide approach to make information about all clinical trials available to the public. Trial registration through ANZCTR has the potential to improve research transparency, facilitate trial participation, avoid research duplication, identify research gaps and promote collaboration.

A recent report by the Department of Health on behalf of the CTPRG recommended that jurisdictions and the Commonwealth collaborate to identify opportunities to improve the ANZCTR’s relevance for participants and researchers and ensure it is regularly updated.39

Aspex Consulting has been engaged by the Commonwealth Department of Health to undertake a review of the ANZCTR and provide detailed advice on practical options to inform a potential next generation clinical trial registry.

37 .NHMRC, Clinical Trials, https://www.nhmrc.gov.au/research/clinical-trials38 . MTPConnect, June 2017, Clinical trials in Australia: the economic profile and competitive advantage of the sector.39 EY, 2016, Scoping and analysis of recruitment and retention in Australian clinical trials: Final Report

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Scope of review

The review will deliver an assessment of the current performance, appropriateness and value for money of the ANZCTR, including current users and uses; the extent that current services are meeting the needs of stakeholders; and alignment to contemporary international and domestic best practice for clinical registries. Based on these findings, the review will develop and test options for a potential next generation Australian clinical trial registry with key stakeholders.

Consultation

The content of this paper is intended to stimulate discussion with stakeholders involved in the ANZCTR review, and any options for improvement in the context of current and future trends in the Australian clinical trials research sector.

The paper poses questions that may be explored during consultation meetings. They are intended as ‘thought starters’ and prompts for considered discussion. Individuals may choose to focus on questions that are particularly relevant to their interests. Similarly, it is appreciated that all questions will not be relevant to every stakeholder.

There will be other matters that are important to different individuals that can and should be raised. In addition to meetings organised with a range of key stakeholders, written comments by these individuals or other interested parties can be submitted to:

[email protected]

Definitions

A clinical trials register is the formal record of an internationally agreed minimum amount of information about a clinical trial. This record is usually stored in and managed using a database. A clinical trials registry is the entity that houses the register, is responsible for ensuring the completeness and accuracy of the information it contains, and that the registered information can be used to link potential participants with relevant clinical trials and inform health care decision making.

This should be distinguished from clinical quality registries, which collect data on the quality of health care provided to patients who use health care resources. This information is used to improve the quality of the health care system by monitoring whether treatments are being utilised appropriately and measuring patient outcomes. Clinical quality registries provide data to jurisdictions, health care providers, clinicians, researchers and others to set clinical performance benchmarks and identify where there are significant variations in health outcomes.40

40 .National arrangements for clinical quality registries. (n.d.). Retrieved February 27, 2018, from https://www.safetyandquality.gov.au/our-work/information-strategy/clinical-quality-registries/

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Discussion points

We are seeking your views on three broad themes:

The appropriateness of the ANZCTR in addressing the current needs of all key stakeholders;

The efficiency of the ANZCTR in capturing a specified range of research activities, maximising the quality and completion of information, and minimising the burden to all stakeholders who utilise or otherwise manage the registry; and

The effectiveness of the ANZCTR as a current and future register of research activities, a source of accessible information to the public, and a comprehensive source of data for researchers, government and other key stakeholders.

These are elaborated further below.

Appropriateness of the ANZCTR

1. What is the current range of government policy and program objectives related to any national clinical trials registry?

2. What are the current objectives of the ANZCTR and how well are these meeting the needs of stakeholders?

3. What agencies or organisations currently rely upon information collected in the ANZCTR?

4. How accessible and useful is information currently held by the ANZCTR to a range of different stakeholders?

5. What additional requirements do stakeholders currently need from any national clinical trials registry?

6. What alternative sources of data, or approaches to collection of information about clinical trials (including innovations), are currently available or might be considered to address the needs of stakeholders?

Efficiency of ANZCTR operations

7. What are the current costs of administering the ANZCTR (to government, the contracted provider, or other benefactors) and how have these changed over time?

8. What are the current processes and governance arrangements involved in operating the ANZCTR?

9. What are the current range of outputs delivered by the ANZCTR on an annual basis (what is the specific quantity, quality, timeliness, and cost)?

10. What factors have helped or hindered the ongoing operation of the ANZCTR?

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11. What opportunities exist to simplify or improve operational implementation of the ANZCTR and how might this best be achieved?

Effectiveness of the ANZCTR and consideration of alternative approaches

12. How well has the ANZCTR achieved its current objectives?

13. What alternative sources, methods, processes or innovations in data collection and dissemination (i.e., options) might be considered to sustain, improve, supplement or replace information currently held by the ANZCTR?

14. What are the foreseeable risks of maintaining the current registry and of moving to any alternative approach to data collection, dissemination and/or reporting?

15. What level of system interoperability is expected, including consistency with relevant standards, capacity to accommodate changes in approaches to research, and innovations in systems architecture and/or software development?

16. What are the options and implications for any future structure, funding, governance, accountability, reporting arrangements, and compliance with current WHO clinical registry criteria associated with collection and management of information about clinical trials in Australia?

17. What are the key steps and indicative timelines associated with maintaining/improving the ANZCTR or transitioning to any new arrangements?

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Appendix 2 List of stakeholders consultedOrganisation Category Date Meeting IndividualsANZCTR ANZCTR 20-Mar & 11-Apr 2 5Consumers Health Forum Australia Consumer group/consumer 16-Mar 1 1Individual consumer Consumer group/consumer 3-May 1 1Individual consumer Consumer group/consumer 17-May 1 1ACT Health Government 4-Mar 1 2Cancer Australia Government 3-Apr 1 1Commonwealth Department of Health Government 14-Mar 1 3Dept of Industry, Innovation & Science Government 15-Mar 1 4NHMRC Government 14-Mar 1 3NSW Department of Health Government 20-Mar 1 2NT Health Government 3-Apr 1 1NZ Health Research Council Government 9-Apr 1 2Queensland Department of Health Government 22-Mar 1 1SA Health Government 28-Mar 1 2Tasmania Health, University of Tasmania, Hospital Government & Research 5-Apr 1 4Therapeutic Goods Administration Government 15-Mar 1 4Therapeutic Innovation Australia Government 4-Apr 1 2Victorian Department of Health & Human Services Government 16-Mar 1 2WA Health & WA Hospitals Government & Research 27-Mar 1 6Medical Technology Association of Australia Industry group 29-Mar 1 1Medicines Australia Industry group 28-Mar 1 6MTPConnect Industry group 19-Mar 1 1ARCS Other agency 20-Mar 1 1Bellberry Other agency 26-Mar 1 1Cancer Council Victoria Other agency 5-Apr 1 1Catholic Health Australia Other agency 14-Mar 1 1ClinTrial Refer Other agency 10-Apr 1 2Australian Clinical Trials Alliance Research 6-Apr 1 1Australian Health Research Alliance Research 3-Apr 1 1Australian Society of Medical Research Trials Alliance Research 9-Apr 1 1Central Australia Academic Health Science Centre Research 5-Apr 1 3George Institute Research 13-Apr 1 1Professor John McNeil, Monash Partners Research 4-Apr 1 1Professor Paul Glasziou, Bond University University 23-Mar 1 1Total 34 68

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Appendix 3 Current IT Infrastructure

The current state of the ANZCTR’s IT infrastructure is described below using The Open Group Architectural Framework (TOGAF), which recognises four interrelated areas of specialisation called architecture domains. These are:

Business architecture, which defines the business strategy, governance, organization, and key business processes of the organization;

Data architecture, which describes the structure of an organization's logical and physical data assets and the associated data management resources;

Applications architecture, which provides a blueprint for the individual systems to be deployed, the interactions between the application systems, and their relationships to the core business processes of the organization with the frameworks for services to be exposed as business functions for integration; and

Technical architecture, or technology architecture, which describes the hardware, software, and network infrastructure needed to support the deployment of core, mission-critical applications.

Business architectureThe ANZCTR runs on IT infrastructure it owns, which is housed in a data centre located on the University of Sydney premises along with non-registry infrastructure. The Clinical Trials Centre (CTC) maintains ANZCTR’s infrastructure on its behalf through a managed service arrangement. The ANZCTR’s internal IT support maintains the registry application software.

For infrastructure issues, CTC’s operational group provides Level 1 support, whilst the ANZCTR IT provides Level 2 and Level 3 support. On average, CTC receives 375 support calls per annum, whilst internal IT receives only two to three support calls per annum.41

CTC manages the IT infrastructure, including software maintenance, for 24x7 availability. Internal support for the Registry is only available during business hours.

All changes that have the potential to impact the operation and availability of the ANZCTR infrastructure are subject to a formal change control process by the CTC infrastructure group. In a similar way, changes to the registry itself are subject to a formal change control by the ANZCTR’s internal IT group. Typically, there is a two-week software release cycle for the registry, although some releases are performed monthly.

Access to the floor housing the server room is controlled via key card entry (restricted to University of Sydney staff), and access to the server room is via a keypad.

41 Level 1 denotes the first support level accountable for basic issues; Level 2 denotes in-detail technical support level; and Level 3 denotes the uppermost level of support in a technical support model accountable for resolving the most difficult problems.

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Data architectureRegistry data is stored in a Microsoft SQL Server 2008 R2 Standard Edition database, which is approximately 1.873Tb in size, with annual growth of approximately 200Mb. There is a separate database housing a data feed from ClinicalTrials.gov, roughly 2Gb in size.

The web application and database are both backed up daily. Backups are rotated offsite on a daily basis.

CTC provide Disaster Recovery capability for the registry using a warm standby approach, whereby the registry is mirrored to a secondary server for redundancy purposes.

Application architectureThe registry has been architected as an n-tier web-based application using the Microsoft .NET framework. This means it has a presentation tier, business tier and data tier, configured as follows:

The presentation tier has been developed in ASP.NET;

The business tier has been developed in the C#.NET programming language; and

The data tier uses a Microsoft SQL Server database to store the registry’s data.

The web application (presentation tier and business tier) runs on a virtual server with a capacity of 2 x CPUs, 8Gb RAM and 500Gb storage, whilst the database runs on a physical server with a capacity of 2 x CPUs, 256Gb RAM and 1Tb of storage.

The registry uses a bespoke search engine based on the Microsoft ’exact match’ search algorithm. There are plans to enhance the registry’s search capabilities by implementing ‘fuzzy’ search and ‘phonetic’ search algorithms, for example. The database contains a copy of ClinicalTrials.gov data poses search challenges because a lot of the fields contain free text.

The registry has three web services, which it uses to connect to NHMRC/DIIS, ANZGOG and a local health service. It replicates to a second database internally. An Application Programming Interface (API) is under development using the SEPTRE web-based protocol building tool for the purpose of exposing data to reduce duplicate entry of data.

Technical architectureThe live registry infrastructure is hosted at Macquarie Telecom in Sydney, with replication to a backup server located physically at the National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC). This server room houses the necessary communications equipment, including switches and firewalls, with details below:

The firewall is a Cisco ASA5525 appliance;

Anti-virus protection is provided by Symantec Endpoint; and

Two commercial grade air conditioners to maintain the server room temperature.

There are redundant telecommunications: one link is supplied by TPG and the other is supplied by the University of Sydney.

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Redundant power is provided by a combination of an uninterruptable power supply (UPS) with 30 minutes reserve power and a backup generator (in the basement of building), which is tested every six months by CTC in conjunction with the University of Sydney.

Data Replication and Backup Server

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Appendix 4 Publications by the ANZCTR

The following publications by the ANZCTR include those completed or submitted since 2015.

Peer-reviewed journal articles

Kelly L, Offringa M and Askie LM, Trial registration in paediatric surgery trials. J Ped Surg 2017 (submitted);

Hunter KE, Seidler AL, Askie LM, Prospective registration trends, reasons for retrospective registration and mechanisms to increase prospective registration compliance: descriptive analysis and survey. BMJ Open 2018; 8: e019983. Doi:10.1136/bmjopen-2017-019983

Korevaar DA, Hooft L, Askie L et al. Facilitating Prospective Registration of Diagnostic Accuracy Studies: A STARD Initiative. Clin Chem. 2017, Aug; 63(8): 1331-1341.

Lam J, Lord SJ, Hunter KE, Simes RJ, Vu T, Askie LM (2015) Australian Clinical Trial Activity and burden of disease: an analysis of registered trials in National Health Priority Areas. Med J Aust. 2015 Jul 20:203(2):97-101.

Other publications (books, book chapters, reports, letters)

Askie LM, Hunter KE Berber S et al. 2017, The Clinical Trial Landscape in Australia 2006-2015, Sydney, Australian New Zealand Clinical Trial Registry

Askie L. Trial registration, updates and protocols [invited correspondence] Lancet 2016: 388 (10042): 341-342.

Tovey D, Bero L, Farquhar C et al. A response to Ian Roberts and his colleagues [Letter]. BMJ, 2015.

Conference papers

Seidler AL, Hunter K, Willson M et al. Comparing the potential for bias between prospectively and retrospectively registered trials in the Australian New Zealand Clinical Trials Registry. Global Evidence Summit:12-16 Sep 2017, Cape Town, South Africa

Seidler AL, Hunter K, Willson M et al. The influence of funding source on study characteristics in the Australian New Zealand Clinical Trials Registry. Global Evidence Summit:12-16 Sep 2017, Cape Town, South Africa

Hunter KE, Seidler AL, Langford A et al. Improving the usability and efficiency of trial registration and updating processes on the Australian New Zealand Clinical Trials Registry, Global Evidence Summit:12-16 Sep 2017, Cape Town, South Africa

Hunter K. Invited speaker. Tackling non-publication bias and poor reporting – the role of clinical trial registries. 24th Cochrane Collaboration: 23-27 Oct 2016, Seoul, South Korea.

Hunter K, Ko H, Askie L. Prospective/retrospective registration trends on the Australian New Zealand Clinical Trials Registry from 2006-2015. Poster at the 24 th

Cochrane Colloquium: 23-27 Oct 2016, Seoul, South Korea.

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Hunter K, Vu T, Sausa R et al. Australian New Zealand Clinical Trials Registry user survey results from 2009-2015. Poster at the 23rd Cochrane Colloquium; 3-7 Oct 2015, Vienna, Austria.

Ko H, Hunter K, Vu T et al. An audit of the data structures of four international clinical trial registries, 23rd Cochrane Colloquium, Vienna, Austria. 3rd – 7th October 2015.

Ko H, Smith E, Zhang L et al. Variation in data structures across four international clinical trial registries (poster). The inaugural REWARD/EQUATOR Conference: September 2015; Edinburgh, UK.

Ko H, Hunter K, Smith E et al. Trends in medical device clinical trials in Australia from 2002 to 2013, 7th International Shared Decision-making (ISDM) and the 4th

International Society for Evidence-Based Health Care (ISEHC) Conference, Sydney, Australia, 19th-22nd July 2015.

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