Potential for efficiency improvements in conducting ...

HealthConsult Pty Ltd ACN 118 337 821

Level 3, 86 Liverpool Street, Sydney, New South Wales, 2000 Phone (02) 9261 3707

16th December 2015

Prepared for the NSW Ministry of Health

Office for Health and Medical Research

Potential for efficiency improvements in conducting clinical trials in

public hospitals throughout Australia

Final Paper

Prepared by HealthConsult Pty Ltd (ACN 118 337 821) for the NSW Ministry of Health Project Team: Joe Scuteri HealthConsult Project Director Lisa Fodero HealthConsult Project Manager Cathy Hoadley HealthConsult Project Consultant HealthConsult Pty Ltd Head Office: Level 3, 86 Liverpool Street, Sydney, New South Wales, 2000 Phone (02) 9261 3707 Email: [email protected]

mailto:[email protected]

Table of Contents

Section Page

EXECUTIVE SUMMARY ........................................................................................................................ 1

INTRODUCTION .................................................................................................................................... 4

SITE AUTHORISATION ......................................................................................................................... 6

2.1 FEASIBILITY ASSESSMENT .............................................................................................................................................................. 6

2.2 ETHICS APPROVAL ........................................................................................................................................................................... 9

2.3 SITE-SPECIFIC ASSESSMENT ............................................................................................................................................................ 9

2.4 SUGGESTED SOLUTIONS ...............................................................................................................................................................10

SITE IMPLEMENTATION ..................................................................................................................... 13

3.1 CLINICAL TRIAL TRAINING ...........................................................................................................................................................13

3.2 DEPARTMENT SET-UP ACTIVITIES ...............................................................................................................................................13

3.3 TRIAL EQUIPMENT SET-UP ...........................................................................................................................................................14

3.4 PRE-SCREENING ACTIVITY ...........................................................................................................................................................14

3.5 DATA ENTRY AND TRANSFER PROCESSES ..................................................................................................................................15

3.6 ADMINISTRATION MANAGEMENT ..............................................................................................................................................16


SITE CLOSE-OUT ............................................................................................................................... 19

4.1 ARCHIVING OF CLINICAL TRIAL RECORDS ................................................................................................................................19


GENERAL STRUCTURE AND PROCESS ISSUES ................................................................................... 20

5.1 SKILLS AND EXPERIENCE OF CTM/C ........................................................................................................................................20

5.2 ESTABLISHMENT OF CLINICAL TRIALS SUPPORT ROLES ..........................................................................................................20

5.3 USE OF CONTRACT RESEARCH ORGANISATIONS ....................................................................................................................22

SUMMARY .......................................................................................................................................... 23

6.1 INVESTMENT IN INFORMATION TECHNOLOGY ........................................................................................................................23

6.2 BETTER USE OF SKILLS IN CENTRALISED DEPARTMENTS .......................................................................................................23

6.3 STRUCTURED PROCESSES FOR SHARING LEARNINGS AND RESOURCES ...............................................................................24

6.4 STREAMLINED SITE-SPECIFIC ASSESSMENT PROCESS ...............................................................................................................24

6.5 STREAMLINED TRAINING .............................................................................................................................................................24

6.6 CENTRALISED ORGANISATIONAL MODELS USING SPECIALIST POSITIONS ..........................................................................25

6.7 DEVELOPMENT OF CLINICAL TRIALS MANAGEMENT PLANS .................................................................................................25

6.8 TRANSPARENT RESEARCH INFRASTRUCTURE FUNDING .........................................................................................................26

Table of Abbreviations

CTC Clinical Trials Centre

CRF Case report form

CRO Contract research organisation

ECG Electrocardiogram

FTE Full-time equivalent

GCP Good clinical practice

HREC Human Research Ethics Committee

IHPA Independent Hospital Pricing Authority

JAC Jurisdictional Advisory Committee

LHD Local health district

MRFF Medical Research Future Fund

NHMRC National Health and Medical Research Council

NMA National mutual acceptance

NSW New South Wales

OHMR Office for Health and Medical Research

PAS Patient administration systems

PI Principal investigator

SHPA Society of Hospital Pharmacists of Australia

SSA Site-specific assessment

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NSW Ministry of Health Page 1 Potential for improvements in conducting clinical trials in hospitals throughout Australia Final Paper

Executive Summary

The context

HealthConsult was engaged on 9th September 2015 by the Office for Health and Medical Research (OHMR), NSW Ministry of Health to prepare a paper on:

“the potential for efficiency improvements in conducting clinical trials in public hospitals across Australia”

Over the past three years, HealthConsult has completed several projects that have enabled us to develop a detailed understanding of the conduct of clinical trials in hospitals in Australia. For all these projects, HealthConsult conducted wide-ranging consultations by visiting hospitals in most states/territories for discussion with staff involved in conducting clinical trials (e.g. oncology, haematology, respiratory, surgery, pathology, pharmacy, governance and finance). Based on the hospital visits and broader industry consultation (e.g. with pharma and biotech, contract research organisations, and research/clinical trial collaboratives), HealthConsult has been able to compare and contrast processes for the conduct of clinical trials across Australia. Using this knowledge, this paper presents HealthConsult’s views about potential areas for improvements in conducting clinical trials in Australian public hospitals. Methodology

Development of this paper involved HealthConsult drawing on information already gathered, and knowledge gained, from projects undertaken for Independent Hospital Pricing Authority (IHPA) and the National Health and Research Medical Council (NHMRC) which include:

Development of a Table of Standard Costs for Conducting Clinical Trials in Australia, undertaken for IHPA in 2013;

Development of a revised List of standard items for the activities associated with conducting clinical trials, undertaken for the NHMRC in 2014;

National Consultation on a ‘Good Practice’ Process for the Governance Authorisation of Clinical Trials, undertaken for the NHMRC in 2014; and

Development of a Table of Standard Costs for Conducting Clinical Trials in Australia, undertaken for IHPA in 2015.

Approval was sought and received by IHPA’s Jurisdictional Advisory Committee (JAC) to use the already gathered information from some 25 public hospitals across Australia to prepare this paper. Suggested solutions for improving the efficiency in conducting clinical trials

Table ES.1 summaries the identified potential areas for improvements in conducting clinical trials in Australian public hospitals, which we believe could result in efficiency gains for both clinical trial funders and trial sites.

Table ES.1: Summary of the suggested solutions for improving the efficiency in conducting clinical trials

Issue Solution Improvement

Lack of, or poor electronic patient level databases.

Unlikely that any one database/system will be able to prevent clinical trials staff having to review some form of paper medical records. However, work could be done by hospitals to reduce this by:

reviewing past feasibility questionnaires to find any frequently requested data elements and ensure they can be captured in the available system;

educate clinicians about the need to include these data elements;

modify systems to include flags requesting these data elements;

ensure the systems/databases in which the data is being entered is searchable and reports can be easily extracted.

Efficiency gains in both the site authorisation (e.g. completion of feasibility questionnaire) and site implementation activities (e.g. pre-screening).

Enable the completion of feasibility questionnaires using actual data which would provide sponsors with realistic expectations on the potential accrual rates by site.

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Lack of computer access available to clinical trials staff.

Increase the number of computers available to clinical trials staff.

In order to work out how many computers are needed, an audit of computer access will need to be undertaken to identify which clinical trials departments/unit have a below minimum access to a computer (e.g. no more than two staff to any one computer).

Funding will be required to solve this issue.

Reduction in time clinical trials staff waste on waiting to get access to a free computer which would enable more timely completion of online training, data entry and other clinical trial reporting requirements and tasks.

Slow and/or poor quality internet speed.

Improve the quality and speed of internet available at clinical trials sites.

An investigation into why public hospitals have insufficient internet speeds will need to be undertaken. Options for improving the quality and speed of the internet will need to be costed. Then funding will need to be identified to solve this issue.

Reduction in the time clinical trials staff spend on: online training; trial equipment set-up; eCRF data entry; upload and transfer of patient results to central repositories, etc.

Different eCRF applications used.

Conduct investigation to understand why different eCRF platforms perform differently (i.e. some less efficient than others) given the known IT issues across all sites.

Identifying what eCRF features and/or software specifications enable certain platforms to be more efficient would be beneficial even if the IT issues (discussed above) are not all resolvable.

State or national body to engage with clinical trials sponsors to explain the efficiency gains by standardising the use of eCRF platforms to either one or two, or providing information on the preferred specifications that will enable their eCRF platforms to be as efficient as possible for clinical trial sites.

Reduction in the amount of time clinical trials staff spend on data entry.

GCP training requirements of clinical trials staff.

The most practical solution would be for either state/territory health departments or a national body (e.g. NHMRC) to engage with sponsors to encourage more of them to become TransCelerate Member Companies.

Reduction of the amount of time in which clinical trials staff spend on regularly repeating unnecessary courses and this would also reduce the need for computer access.

No or limited sharing of learnings, processes and developed resources.

Create a forum focused on sharing learnings from conducting clinical trials and sharing of developed resources. Although there would be benefit in establishing these forums at state/territory and/or national level, the solutions are likely to be site specific or LHD (or equivalent) specific.

Engage with industry sponsors to understand their needs (e.g. in the budget workup how much detail etc. do they need).

Development of standardised processes and resources (at least at a hospital level) that meet both the sites and sponsor’s needs.

Reduction in the amount of time spent by many departments within a hospital replicating the development of similar processes and resources.

Reduction in time spent by sponsors requesting additional information and reduction in time spent by clinical trials staff producing information that is not meeting sponsor’s needs.

Limited engagement of finance department.

Establish a series of meetings at each hospital where clinical trials staff meet with finance personnel to discuss the various financial aspects involved in conducting clinical trials. These meetings will enable a shared understanding of where the finance department can utilise their expertise to assist in improving the efficiency of conducting clinical trials.

Reduction in time spent by clinical trials staff on financial aspects of conducting clinical trials.

Establishment of dedicated cost centres for each clinical trial to enable analysis that can be used by departments/sites, to inform their participation in future clinical trials.

Streamlining of clinical trials financial reports.

Limited overarching hospital management and engagement.

Conduct further investigation into the various management models that have been implemented across Australia and share the pros and cons of each model and promote the most efficient model.

Research into, and then promotion of an efficient and supportive clinical trials management model, will assist hospitals involved in conducting clinical trials, with an evidence base to leverage off.

Encourage all sites to develop clinical trials hospital management plans, which articulate the processes and available resources for clinical trials, which all clinical trials units in a hospital should be involved in (and sign up to). Development of such a plan would benefit from a leadership body (e.g. state/territory health department or national body like NHMRC) to engage with the hospitals, provide a standardised template for all hospitals to complete (that describe the suggested meetings to be had, the information to be sought, and include an action plan with nominated personnel/department charged with implementing).

On completion of each hospitals clinical trials plan, have a forum where their plans can be shared across the LHD (or equivalent) or state/territory to see if any activities can be undertaken by the leadership body (either LHD or state/territory health department or NHMRC) so that they can be standardised across the state or nationally.

Promotion of the development of clinical trials management plans will assist in streamlining processes (and resources) involved in conducting clinical trials within hospitals and possibly across the state/territory or nationally.

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Review of state-specific additional HREC requirements.

Investigate the reasons for the additional and varied requirements in the completion of the HREC documentation when sites from one specific jurisdiction are involved in clinical trials. Such an issue should be raised at an appropriate national forum to understand the reason for the additional and varied requirements.

Reduce HREC fees being paid by sites and/or sponsors

Reduce clinical trials and governance office staff, sponsors and ethics committee time in preparing and/or reviewing additional ethics application.

Unnecessary and duplicative inclusions in site-specific assessment (SSA).

Identify interventions that are part of standard of care and included in the clinical trial protocol. If there is no modification to the standard of care procedure then consider excluding the need for each site to obtain the necessary documentation for inclusion in each sites SSA process.

Identify areas of duplication between the ethical review and governance review processes; assess each identified area separately as to whether they need to be in the ethical review only, governance review only or both.

Review the SSA process to identify if all sites need to gather all currently requested information or if certain parts can be delegated to either the (1) lead site only; (2) one site within each state/territory; (3) one site within each LHD (or equivalent); or (4) all sites.

Reduction in time spent by all clinical trials sites in gathering proof for standard of care interventions included in clinical trials protocols;

Potential reduction in ethics office staff and HREC members if process results in removing duplication between ethics and governance processes.

Transparency in research infrastructure funding

In addition to pursuing the identified opportunities, there is also a need to provide more transparency in the funding of clinical research in the public hospital system. Research funding, particularly the funding of the organisational capacity in hospitals that makes doing clinical trials feasible, has always been difficult to identify. For some purposes, guesstimates are made by using what is normally an arbitrary (i.e. not well-tested formula) that expresses research funding as a percentage of total funding. But, in reality, as public hospitals have come under increasing pressure to balance budgets in the face of increasing demand, there is a widely held view that the proportion of the hospital’s operating budget that supports clinical research has diminished very considerably. As a consequence, public hospitals, in their quest to ensure that clinical research continues to be available at their organisation, have sought to identify other methods of funding. This quest has resulted in the cross-subsidisation of non-sponsor funded clinical research by funds derived from industry sponsored clinical trials. In particular, industry sponsors believe that the fee increases relating to clinical trials in Australia are, at least partly, due to the fees being used to cross-subsidise poorly funded (e.g. collaborative sponsored trials) or non-funded (e.g. investigator initiated) clinical trials. That said, all stakeholders involved (including industry), want to see good quality clinical trials available to patients in Australia. The Federal Government’s current policies that emphasise health and medical research (including the Medical Research Future Fund (MRFF)) may translate to more funding available in public hospitals for clinical research. That outcome could provide more funding for investigator initiated trials, thereby allowing public hospitals to set their clinical trials fees closer to actual cost for industry sponsored trials. But, if fees are set at levels noticeably greater than costs, then industry sponsors are likely to demand outcomes based payment models, which will put more pressure on the already struggling clinical trials infrastructure and staff. This move will likely result in further increases in fees by public hospital clinical trials sites, which might mean fewer good quality clinical trials being available to Australians. The best solution is to make research funding in public hospitals transparent, whatever the source of funds.

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1 Introduction

HealthConsult was engaged on 9th September 2015 by the Office for Health and Medical Research (OHMR), NSW Ministry of Health to prepare a paper on:

“the potential for improvements in conducting clinical trials in hospitals across Australia” This Chapter sets out the project context and methodology. 1.1 PROJECT CONTEXT

Over the past three years HealthConsult has been involved in several projects that have enabled us to develop a detailed understanding of the conduct of clinical trials across more than 25 hospitals in Australia. These projects include:

Development of a Table of Standard Costs for Conducting Clinical Trials in Australia, undertaken in 2013 for the Independent Hospital Pricing Authority (IHPA);

Development of a revised List of standard items for the activities associated with conducting clinical trials, undertaken in 2014 for the National Health and Medical Research Council (NHMRC);

National Consultation on a ‘Good Practice’ Process for the Governance Authorisation of Clinical Trials, undertaken in 2014 for the NHMRC; and

Development of a Table of Standard Costs for Conducting Clinical Trials in Australia, undertaken in 2015 for IHPA.

For all these projects, HealthConsult conducted wide-ranging consultations by visiting hospitals in most states/territories for discussion with staff involved in conducting clinical trials (e.g. from oncology, respiratory, pathology, pharmacy, surgery, governance, and finance). Based on the hospital visits and broader industry consultation (e.g. with pharma and biotech, contract research organisations, and research/clinical trial collaboratives), HealthConsult has been able to compare and contrast processes for the conduct of clinical trials across Australia. Using this knowledge, this paper presents HealthConsult’s views about potential areas for improvements in conducting clinical trials in Australian public hospitals, which we believe could result in efficiency gains for both clinical trial funders and trial sites. 1.2 PROJECT METHODOLOGY

To draft this paper HealthConsult drew on information gathered and the knowledge gained from our IHPA and the NHMRC projects. Our methodology for developing the paper included:

a project planning meeting with the OHMR project team to ensure there was a clear understanding on the expected deliverable;

seeking and receiving approval from IHPA’s Jurisdictional Advisory Committee (JAC) to use previously gathered information to prepare the paper;

notifying sites involved in the 2015 IHPA project about the report and advising them of the JAC approval to use the gathered information;

reviewing and analysing the already gathered information to produce the first draft paper; providing the draft paper the OHMR project team for review and comment; and making changes to the draft paper to address the feedback received, then handing over the final paper

to the OHMR project team.

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1.3 STRUCTURE OF THE REPORT

The structure of this paper is based on the structure of the revised Standard List of clinical trials developed by the NHMRC, which is organised according to the three typical stages in the clinical trial lifecycle at a trial site (i.e. Site Authorisation, Site Implementation, and site close-out). Figure 1.1 provides an overview of the clinical trial lifecycle including the high level clinical trial activities included in each stage (see information in grey boxes).

Figure 1.1: Illustration of the structure of the revised Standard List of items associated with clinical trials

The structure of the remainder of the paper is:

Chapter 2 describes the similarities and differences in processes observed in hospitals undertaking site authorisation processes, identifies inefficiencies and suggests possible solutions;

Chapter 3 describes the similarities and differences in processes observed in hospitals undertaking site implementation processes, identifies inefficiencies and suggests possible solutions;

Chapter 4 describes the similarities and differences in processes observed in hospitals undertaking site close-out processes, identifies inefficiencies and suggests possible solutions;

Chapter 5 describes some more general structure and process issues related to the conduct of clinical trials that are not specific to any phase of the trial lifecycle, and suggests possible solutions; and

Chapter 6 presents a summary of the suggested solutions for improving the efficiency of the conduct of clinical trials in Australia public hospitals.

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2 Site Authorisation

Site authorisation of a clinical trial involves all activities from the first contact with a trial sponsor, through to carrying out a feasibility assessment and gaining ethics and site-specific assessment (SSA) approvals. This Chapter describes the key variations identified in undertaking the site authorisation processes, identifies inefficiencies and suggests possible solutions. 2.1 FEASIBILITY ASSESSMENT

This section describes the current practices across Australia for the key activities associated with sites undertaking a clinical trial feasibility assessment including completing the feasibility questionnaire, budget negotiation and contract review. 2.1.1 Completion of feasibility questionnaire

The processes involved in assessing feasibility of a clinical trial varies by departments within hospitals and across hospitals. The variation described in this section is consistent across states (i.e. no one described scenario is specific to any one state or territory in Australia). In regards to the completion of the feasibility questionnaire, the observed variation relates to which personnel are involved in the completion and/or review of the feasibility questionnaire; and how much time is required to complete the feasibility questionnaire. The different scenarios observed included:

Scenario 1: potential principal investigator (PI) and clinical trials manager/coordinator (CTM/C) have a quick five minute discussion as to whether they are interested in the clinical trial. If so, the CTM/C completes the feasibility questionnaire with minimal input from the potential PI and best guess estimates are included in the questionnaire responses (i.e. medical records are not accessed);

Scenario 2: potential PI presents the clinical trial synopsis at a multidisciplinary departmental meeting or at a specialty specific clinical trial meeting (such as oncology or haematology). A decision is made at that meeting as to whether the group is interested in the clinical trial. If so, the CTM/C completes the survey with some input and review from the potential PI and best guess estimates are included in the survey responses (i.e. medical records are not accessed);

Scenario 3: involves scenario 1 plus electronic medical records (including speciality/department patient databases) sourced for information;

Scenario 4: involves scenario 1 plus electronic (including speciality/department patient databases) and paper based medical records sourced for information;

Scenario 5: involves scenario 2 plus electronic medical records (including speciality/department patient databases) sourced for information; or

Scenario 6: involves scenario 2 plus electronic (including speciality/department patient databases) and paper based medical records sourced for information.

The time and hence cost variation identified by the scenarios is impacted by the comprehensiveness of the questionnaire and whether actual data were sourced to complete the feasibility questionnaire.

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The scenario used by individual hospital departments was based on specific departmental practices rather than hospital policies. However, the need to access medical records (paper or electronic) is related to the complexity of the questionnaire, the target population and the phase of the clinical trial, for example:

Complex feasibility questionnaires which contain questions in regards to very specific clinical trial criteria usually resulted in someone having to access medical records.

Large target populations such as breast cancer patients did not usually require access to medical records, as the oncology staff would be able to provide a reasonable guesstimate. However for clinical trials wanting to recruit patients with specific breast cancer genetic mutations, review of the medical records (either via an electronic search of clinician specific or departmental or hospital database, but usually through review of paper medical records) is necessary.

Sites reported that less time was required to assess feasibility of Phase 2 and 3 clinical trials as opposed to Phase 1 or 4 clinical trials.

F1: The ability for clinical trials sites to efficiently complete comprehensive feasibility

questionnaires is impacted by the lack of comprehensive electronic patient databases. In addition, a number of sites reported being asked to complete feasibility questionnaires for clinical trials from multiple contract research organisations (CROs) bidding for work from the same trial sponsor. Even if it is obvious that the approach is for the same potential clinical trial, hospitals still need to complete the variations of the feasibility questionnaire to ensure that their patients have access if, and when, the trial goes ahead with whichever CRO has been successful in obtaining the contract. F2: Clinical trials sites are wasting time completing feasibility questionnaires provided by

multiple CROs for the same clinical trial. In contrast, some sponsors reported a preparedness to fund sites to complete comprehensive feasibility questionnaires if actual data are sourced. However, most sites respond that they are unable to access the data from the available systems. It is important to note that the reasons sponsors are offering funding for this previously unfunded task is due to low patient recruitment rates which do not align to the numbers indicated by sites on the feasibility questionnaires (which are based on best guess estimates). F3: Clinical trials sites struggle to source data to provide an accurate estimate of the number

of potential clinical trials participants that meet the exclusion/inclusion criteria on the feasibility questionnaires.

2.1.2 Budget negotiation

Again, the process of budget negotiation varies within departments of hospitals and across hospitals. Most of the variation is dictated by the type of sponsor:

For collaborative trials and some industry sponsored trials (e.g. pharmaceutical or device companies), the budget was more than often set, and there was no negotiation. Then, the role of the site was more about assessing whether or not they would undertake the clinical trial for the set budget.

For other industry sponsored trials sites are increasingly being asked to either complete a sponsors budgeting template, which guides a ‘bottom up’ type of costing approach, or to use their own internal (usually departmental) processes to start the price negotiation with the sponsor.

The amount of time spent by various personnel on budget negotiation varied, and the process was also considerably more complicated and drawn out (i.e. additional input time required) if a CRO was involved, as opposed to negotiating directly with the trial sponsor. Some departments have developed their own costing and/or budgeting templates that have been tested and refined over the years. Other departments

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and/or hospitals use the provided sponsor/CRO templates. Yet others were unaware that departments within their hospitals used or had developed such templates. F4: Some departments within hospitals have developed their own costing and/or budgeting

templates that have been tested and refined over the years. Other departments/hospitals use the provided sponsor/CRO templates. Yet others were unaware that departments within their hospitals used or had developed such templates.

F5: The amount of time sites spend negotiating clinical trials budgets with clinical trials

sponsor is increased if a CRO is involved. The involvement of staff with experience in costing and/or budgeting (e.g. from the hospital’s finance department) in developing clinical trial budgets for use in the negotiation process varied from no participation through to a dedicated person in the finance department whose role it is to support clinical trials. Often CTM/C and PIs are ‘learning on the job’ how to cost a clinical trial and negotiate a budget with a sponsor. Although the finance departments are often found not to be involved, most sites have at least one department within the hospital that has very experienced staff (e.g. usually in oncology and/or haematology) that have developed templates for working up clinical trials budgets. In addition, most supporting departments (particularly pharmacy) have developed a schedule of fees, which is used as the basis of charging industry sponsors. In fact, the pharmacy clinical trials fee schedule is published by the Society of Hospital Pharmacists of Australia (SHPA). It is important to note that the fees published by SHPA do not necessarily represent the costs incurred, as to the best of our knowledge no costing study was undertaken as the basis for setting the fees. In fact most clinical departments involved in conducting clinical trials operate as silos with no or limited sharing across departments within the same hospital let alone across hospital sites. Some departments in some hospitals had no knowledge that other departments had developed fee schedules; or that there was even the possibility of receiving some financial compensation for participating in a clinical trial; or that you could negotiate a budget. F6: There is limited support provided to clinical trials staff in the construction of clinical trials

budgets by staff experienced in costing and/or budgeting. F7: Some departments (more experienced in clinical trials budget negotiation e.g. oncology

departments, pharmacy department etc.) within hospitals have developed a schedule of fees they refer to when working up their clinical trials budget. Most fees have no reference to actual costs. Some departments without fee schedules were unaware such schedules existed within their hospital.

2.1.3 Contract review

Sites reported that the process of contract review is efficient if a standard contract (like Medicines Australia or Medical Technology Association of Australia agreement or another pre-approved agreement) is used with pre-approved schedules. However if the sponsor uses a variation to the standard contract or modifies any of the pre-approved schedules, then the contract needs to be reviewed by legal personnel (either sourced internally or externally). Some departments mandate that if a sponsor wants their hospital to participate in a clinical trial then only Standard Agreements and pre-approved schedules can be used. This position seems to only be taken by departments in high demand for running clinical trials. F8: The process of contract review is efficient if a standard contact (e.g. Medicines Australia

or Medical Technology Association of Australia) with pre-approved schedules is used. If

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variations to the standard are needed, then legal personnel are required, which results in additional staff becoming involved and delays the sign-off of a clinical trial.

Support provided to departments in contract review by the governance office varied. The difference was not necessarily due to an unwilling or unavailable (in terms of competing governance staff priorities) governance office, but more to do with processes within clinical trials departments themselves. Some departments had little contact with the governance office at this stage. Other departments involved the governance office as soon as they were contacted about a clinical trial. F9: Support provided by the governance office in the contract review process varied from no

support sought to early engagement and collaboration with the governance office staff. 2.2 ETHICS APPROVAL

The processes, the number of personnel, and the total time involved in hospitals preparing clinical trials ethics submissions varies. The variation is partly due to sponsor type:

For most industry sponsored trials, sites are provided with a draft HREC application and supporting documentation, which usually only needs minor amendment if it is a good quality draft; or

For investigator initiated and collaborative sponsored trials, as well as for poorly drafted HREC applications and supporting documentation provided by industry sponsors, the lead site usually drafts the HREC application and supporting documentation de novo.

Considerable work has been undertaken in recent years to streamline ethics approval processes across Australia. The most successful of these processes is that most sites across Australia now accept one properly constituted HREC approving the clinical trial (‘the process is called ‘national mutual acceptance’ (NMA)) and progress the SSA process. This change has made the ethics process more efficient as only one HREC considers the application as opposed to multiple. However, a number of sites consulted (including sites from the jurisdiction that has the additional HREC requirements) felt that NMA is not working if clinical trial sites from one particular state is included in a HREC application where the lead is from a state/territory that does not have varied HREC application requirements. This situation is due to the different requirements in this particular state that require the completion of additional jurisdictional-specific sections to the HREC application. For this reason, sites in jurisdictions that do not have these additional requirements refuse to either be a lead site (if a site from the jurisdiction with the additional requirements is going to be included in the clinical trial) or request the sponsor organisation contract them as a single site. When sponsors contract a single site, the streamlining process of one HREC approval for clinical trials in Australia is lost. F10: States/Territories requiring variation in the completion of HREC documentation is

destabilising the national mutual acceptance process, which is reversing the efficiency gains that were emerging from this process.

2.3 SITE-SPECIFIC ASSESSMENT

Generally, the completion of the SSA application was considered a straight forward process at most sites, especially by those departments that had experience in doing them. However some sites suggested a review of the SSA process with the aim to reduce unnecessary processes. For example:

remove the need to provide some of the same information for ethics review (i.e. information/documentation provided to HREC) and then for governance review (i.e. SSA requires information/documentation already provided to HREC);

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remove the need to gather documentation to support radiation and biosafety approval for interventions included in the clinical trial protocol that are part of standard of care (e.g. x-ray, CT scans etc.).

The other main challenges reported with SSA applications was:

the amount of time spent in obtaining the required signatures from all those involved in the clinical trial; and

change in SSA processes due to restructures (e.g. newly created structures for either research institutes or pathology laboratories) so governance processes are more complicated, as these organisations now exist as an entity outside the clinical trial site (e.g. hospital).

F11: Most sites considered the SSA process to be straight forward. However some sites

suggested there should be a review of the SSA process with the aim to reduce unnecessary processes (e.g. reduce duplication between HREC and SSA, and remove the need to gather information to support radiation and/or biosafety approval for interventions included in the clinical trial protocol that are part of standard of care).

2.4 SUGGESTED SOLUTIONS

The bolded numbered findings in the above sections of this Chapter highlight areas of potential inefficiency in the site authorisation activities associated in the conduct of clinical trials. This section suggests some possible solutions to improve processes that could be considered by sites. 2.4.1 Investment in clinical databases

All hospitals have patient administration systems (PAS) that contain a ‘clinical notes” section. We found that hospitals either do not use these fields consistently or they cannot be systematically searched to assist with completing feasibility questionnaires or for pre-screening patients against the clinical trials protocol inclusion/exclusion criteria. Specific departments and/or clinicians within hospitals often have their own patient databases, which usually contain more detailed information than any PAS. However these databases are often not accessible to anyone outside the department and/or clinicians rooms. With the increasing specificity of the clinical trials protocol inclusion/exclusion criteria, it is unlikely any one database/system will be able to prevent clinical trials staff having to review patient medical records (including the results history). However, work could be done by hospitals to reduce this need by:

reviewing past feasibility questionnaires to find any frequently requested data elements and ensure they can be captured in the available system;

educate clinicians about the need to include these data elements;

modify systems to include flags requesting these data elements;

ensure the systems/databases in which the data are being entered can be systematically searched and reports can be easily extracted.

Investing in these processes would result in efficiencies in both the site authorisation (e.g. completion of comprehensive feasibility assessment questionnaire) and site implementation (e.g. pre-screening activity) processes. It would also enable feasibility questionnaires to be completed using actual data, which would provide sponsors with realistic expectations on the potential accrual rates by site. 2.4.2 Training and sharing of clinical trials experiences

As proven by the extensive consultation undertaken with clinical trials sites on activities involved in authorising, implementing and closing out clinical trials, many processes are the same regardless of the phase or type of clinical trial (although it is noted that time and cost may vary). Except for some sites

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which have developed hospital-wide ‘start-up specialist’ positions, no hospital visited had a mechanism where learnings and/or processes used in conducting clinical trials across departments could be shared. It is noted that there are formal qualifications that can be obtained in clinical trials research (e.g. University of Sydney - Graduate Certificate in Clinical Trials Practice; University of Sydney - Graduate Diploma in Clinical Trials Research; and Sydney Medical School - Master of Clinical Trials Research). However formal training is not a substitute for the value that could be gained by bringing together CTM/Cs from all departments within a hospital to identify common processes that if centralised could result in immediate efficiency gains. Examples of common processes involved in conducting clinical trials that could result in potential efficiency gains across a whole public hospital include:

Templates, processes and/or standard costs (not fees) used to construct the clinical trials budget;

Templates and/or processes used to track clinical trials costs and generate and track invoices;

Preparation and submission of ethics applications;

Preparation and submission of SSA applications;

How to use the various software applications involved in the conduct of clinical trials;

IT infrastructure issues and potential solutions to manage them (if any);

Problems that have occurred at any stage of the clinical trial life cycle and solutions identified;

How to utilise and/or engage with the finance department to assist in the budgeting and expenditure monitoring associated with clinical trials;

How to utilise and/or engage with the human resources department to assist in the managing of clinical trials.

Some of these issues could be discussed at state/territory forums, however solutions are likely to be site or LHD (or equivalent) specific. Although sharing the proposed clinical trial budgets between clinical trials sites will breach their signed confidentiality agreements with sponsors, there is no reason that training of clinical trials personnel within the same hospital on how to undertake clinical trials activities cannot be shared. 2.4.3 Engagement with industry to reduce multiple approaches to hospitals

Due to the processes involved in CROs obtaining work from pharmaceutical, biotechnology, and medical device industry clinical trials sponsors, it is likely sites will continue to receive requests for completion of feasibility questionnaires from multiple CROs bidding for the same work (i.e. one clinical trial). As clinical trial sites do not want to miss out on being included in a clinical trial they are likely to continue to complete multiple (although slightly different) feasibility questionnaires. One solution would be to streamline the approaches made to potential clinical trials sites from CROs (and sponsors) to a central point of contact within each public hospital. Although this would provide a way to identify multiple feasibility questionaries for one potential clinical trial, it is unlikely to reduce the clinical trials staff workload (as sites will still want to respond to ensure their site is considered an option by the winning CRO) and is unlikely to be well received by clinicians. An alternative solution would be for either a national body or state/territory health departments to lobby industry sponsors to change the way they engage CROs. Or preferably, for a national body or state/territory departments to begin dialogue with CROs and industry sponsors about this issue with the aim to at least reduce the number of approaches hospitals receive about the same clinical trial. Ultimately such practice results in hospitals having higher costs to establish clinical trials in Australian hospitals.

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2.4.4 Review of state-specific additional HREC application requirements

There is a need to investigate the reasons for the additional and varied requirements in the completion of the HREC documentation when sites from a particular jurisdiction are involved in clinical trials. Such an issue should be raised at an appropriate national forum to understand the reason for the additional and varied requirements. As a result of such discussions, hopefully the issue can be resolved so as to prevent sites without the imposed additional requirements requesting the sponsor organisation contract them as a single site. The impact of sites being contracted as a single site results in more than one site spending time in drafting and submitting an ethics approval. This not only doubles the personnel involved but also increases the cost to the sponsor who is required to pay for more than one HREC fee. 2.4.5 Review of the SSA documentation and processes

Conduct a review the SSA documentation and process to:

Identify interventions that are part of standard of care and included in the clinical trial protocol. If there is no modification to the standard of care procedure then consider excluding the need for each site to obtain the necessary documentation for inclusion in each sites SSA process. This action will ensure all clinical trials sites are not spending time gathering proof that radiation and/or biosafety levels are within tolerance limits for interventions routinely undertaken.

Identify areas of duplication between the ethical review and governance review processes; assess each identified area separately as to whether they need to be in the ethical review only, governance review only or both. This action will reduce not only the time of each site gathering the information but also time spent by HREC and governance office staff reviewing the information.

Review the SSA process to identify if all sites need to gather all currently requested information or if certain parts can be delegated to either the (1) lead site only; (2) one site within each state/territory; (3) one site within each LHD (or equivalent); or (4) all sites. This action may identify areas of the SSA process that can be streamlined so that less sites and governance offices are processing the same information.

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3 Site Implementation

Site implementation of a clinical trial involves all activities from the site start-up meetings, patient screening and recruitment activity, administration and coordination of the trial, personnel input time through to any amendment processing. This Chapter describes the key variations identified in undertaking the site implementation processes, identifies inefficiencies and suggests possible solutions. 3.1 CLINICAL TRIAL TRAINING

All personnel at hospitals involved in clinical trials are required to undertake training prior to the recruitment of the first patient. In addition to personnel being trained in the clinical trial protocol (which occurs either at the site initiation visit or online), online training for other aspects of the clinical trial need to be completed by key personnel involved in the clinical trial. Sites reported that undertaking online training is increasing and becoming more onerous, and less training is being provided at the site initiation visit. The types of online training modules key personnel are required to undertake include:

Clinical Trial Protocol training; Good Clinical Practice (GCP)1; Case Report Form (CRF)2. Both the protocol and CRF training is specific to the clinical trial and clinical trials staff recognise that it needs to be completed prior to the trial starting. However GCP training is not specific to any one trial but a requirement for all research involving patients, not just clinical trials. Initial GCP training takes between 8-10 hours and then refresher courses take between 2-4 hours (depending on how many online screens are skipped). How often refresher courses are required is based on state/territory or hospital policy. However, some sponsors require staff involved in clinical trials to undertake their GCP training course regardless of when they received their latest GCP certificate. For some clinical trials staff in departments that run a lot of clinical trials, this means staff could undertake GCP training several times per year. Some effort has been made by some clinical trial sponsors (mainly the pharmaceutical industry sponsors) to recognise other providers of GCP training and not require hospital staff to undertake their course if the latest course they completed was in x period (x varies dependent on the sponsor). F12: Lack of recognition of GCP certificates by all clinical trials sponsors results in clinical

trials staff having to unnecessarily repeat non-specific clinical trial training. 3.2 DEPARTMENT SET-UP ACTIVITIES

Prior to a clinical trial beginning in any involved hospital department, clinical trial specific processes and documentation need to be prepared (e.g. preparing trial specific request forms, coordination with investigators and/or meeting with sponsors, instructions and identification of locations for storage of samples, development of supporting documentation, and any necessary preparation of medical records). Most of these tasks are largely the responsibility of the CTM/C however supporting departments (e.g. pharmacy, pathology, imaging, and medical records) also have departmental set-up activities they need to

1 Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. 2 A CRF is a document (which may be printed or electronic) which is designed to record all the protocol required information to be reported to the sponsor on each trial subject.

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complete prior to the clinical trial starting (e.g. clinical trial specific folders which describe procedures for processing diagnostic test requests for trial patients, and information about how the clinical trial protocol varies from ‘standard preparations, tests or reporting of results’). A number of the sites reported that the level and standard of source documentation that is being provided by sponsors is deteriorating. This trend is creating additional work for the sites to generate and develop the templates and documentation required during the departmental set-up phase, which in turn requires additional time to be applied to these activities. F13: Reduced levels of, or poor quality, source information provided by Sponsors impacts on

the amount of time clinical trials staff spend on getting departments ready for the commencement of a clinical trial.

3.3 TRIAL EQUIPMENT SET-UP

Sites hosting clinical trials often have equipment that is provided by the sponsor for use during the trial (e.g. centrifuges, weight scales, and electrocardiogram (ECG) machines). Depending on local hospital policy, equipment almost always needs to be checked by biomedical engineering staff prior to the machine being able to be used. A number of sites are frustrated with the processes involved in setting up some of the equipment, mainly the ECG machine. While using the machine was not the issue, it was the time it took to complete the test transfer of data to a central repository. The variability in time it took to perform initial set-up was dependent on the internet connection speed and the quality of the guidance information provided. Depending on the equipment, IT staff were also sometimes required to connect the equipment to the hospital network. F14: Sites often have ECG machines provided by the sponsor. Sites spend considerable time

undertaking the set-up of such equipment, which involves the transfer of data to central repository, due to poor internet speed and quality available at hospitals.

3.4 PRE-SCREENING ACTIVITY

Identification of potential patients to be invited to participate in the clinical trial is a time consuming process for most trials. It is becoming more time consuming with the increasing level of specificity in the inclusion/exclusion criteria for more recent trials. The time it takes for clinical trials staff to identify and then pre-screen patients as to whether they meet the clinical trials specific inclusion/exclusion criteria is impacted by the lack of patient databases by which CTM/C or PI can search to identify patients. F15: The amount of time spent by sites identifying and then pre-screening patients against

the clinical trial’s specific inclusion/exclusion criteria is increased by the lack of electronic patient databases.

Also, the lack of, or limitations in, existing databases is impacting the determination of the actual denominator of patients within any site that meet the inclusion/exclusion criteria. The inability of sites to provide a more realistic denominator to sponsors, particularly industry sponsors, is resulting in sponsors wanting to move to an outcomes based funding model, which sites do not favour. From the sponsors’ perspective, an outcomes based funding approach would provide them with more assurance on the likely recruitment numbers at each site and offer sites more incentive to ensure that the numbers of potential participants they include on the feasibility questionnaire is as close to actual as possible. From the sites’ perspective, they do not want to be penalised for their lack of systems and the resultant extra time required to complete feasibility questionnaire with actual data and want to ensure the time they spend in pre-screening is funded. Some sponsors already offer payment to sites if feasibility

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questionnaires are completed using actual data. In some instances, the payment is refused because the data are not easy to access, which provides further evidence that lack, or limitations, of systems is a critical factor to ensuring realistic expectations on the potential participant numbers in Australian clinical trials sites. At the end of the day, sponsors need to be able to have a sufficient ‘n’ in each trial group to prove their intervention works (whether it be a drug, device, service model). F16: The difference between expected and actual clinical trial participants is resulting in

sponsors wanting to implement outcomes based funding models for clinical trials, which sites do not favour.

3.5 DATA ENTRY AND TRANSFER PROCESSES

Sites reported that there is an increasing need for them to upload digital images (e.g. computerised tomography scans) and other forms of results to central repositories of sponsors. Due to the available IT infrastructure and the quality of the internet connection speed at many hospital sites, this requirement is impacting on the efficiency of various departments (e.g. radiology, pathology, pharmacy) involved in conducting clinical trials throughout Australia. In addition to the upload of results, pharmacy departments need regular access to the sponsors’ central databases to perform all the drug accountability requirement activities (e.g. data entry is required for dispensing of drugs, and on returned and destroyed drugs). CTM/C also enter CRF data regularly on the patients enrolled in the clinical trials. Both pharmacy departments and CTM/C at numerous sites reported that simple tasks can take an extra ordinary amount of time due to IT connection issues. F17: The amount of time spent by sites uploading results and entering clinical trial data to the

central repository of sponsors is impacted by the quality of IT infrastructure (including the available internet connection speed) available at clinical trials sites.

CTM/C at a number of sites reported that there are not enough computers in their department/units for clinical trials staff, which results in them waiting for computers to become free to undertake training, data entry, other reporting requirements and administrative tasks associated with managing the clinical trials. As most departments do not just run clinical trials, other departmental staff have to access the computers and it is not possible for CTM/C to utilise the computer for long periods of time. F18: CTM/C report a lack of access to computers, which results in inefficiencies as they wait

around and are unable to efficiently undertake training, data entry, other reporting requirements and administrative tasks associated with conducting clinical trials.

In addition to the local IT limitations, clinical trials sites reported that the platform on which the eCRF software operates, which may differ by sponsor, can have a significant impact (i.e. either dramatically increase or decrease) on the amount of time it takes to enter the required data (e.g. variation from 10 minutes to two hours to enter a similar amount of data). Some departments try to find out which platform the eCRF will being running on as part of their feasibility assessment process as it has some influence on their decision to participate in a clinical trial. One known variation between eCRF systems is the difference in data entry assurance sought by some software applications (e.g. assurance check done on each data point at time of entry vs. assurance check done at the completion of an eCRF entry (i.e. once per patient)). F19: The eCRF software platform used by different Sponsors can have a significant impact

(i.e. either dramatically increase or decrease) on the amount of time it takes to enter clinical trials data.

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3.6 ADMINISTRATION MANAGEMENT

Most departments involved in the conduct of clinical trials within a hospital operate as discrete entities and they receive little, if any, support from the administrative departments of the hospital such as finance and human resources. CTM/Cs are good at managing clinical trials however almost all reported difficulty with the ability and time to track costs associated with running of the clinical trial, generating and tracking the payment of invoices and recruiting required personnel. This situation means that clinical trial staff who are unlikely to be trained in finance and/or recruitment are spending considerable time doing administrative tasks better suited to other staff in the hospital; and each department undertaking a clinical trial is replicating the same tasks. As clinical trials only involve a small portion of the patient population within a hospital, they are a low priority from a systems perspective and often times labour intensive work arounds become common place for clinical trial administrative processes and management. F20: Almost all clinical trials staff are not trained in finance and human resources and are

undertaking such tasks, with which more experienced staff from relevant departments (e.g. finance and human resources departments) could assist.

Due to the limited support being provided to clinical trials units, very few have developed any mechanism for tracking the costs incurred or profit made on any of their clinical trials. In fact very few finance departments reported to have developed cost centres specifically for management of clinical trials funding. For example, for clinical trials being run out of the haematology department, the trial funding is allocated to the haematology department, and there is no way to identify if the clinical trial funding covered site costs or not. Some sites were more sophisticated and had at least created cost centres for clinical trials even though they were not segmented for each clinical trial (i.e. just one cost centre for all clinical trials run in a given department). There were very few (although some) departments (usually oncology and haematology) that had worked with the finance department to create unique cost centres for each clinical trial, which allowed them to integrate their data to identify clinical trials (or sponsors) where they lost money, were cost neutral or made profit. F21: Most clinical trials units do not track their costs incurred or profit made on any of their

clinical trials. The ability of clinical trials units to know whether they lost money on a clinical trial were cost neutral or made profit was limited to only a few departments.

3.7 SUGGESTED SOLUTIONS

The bolded numbered findings in this Chapter highlight areas of potential inefficiency relating to the site implementation activities associated with the conduct of clinical trials. This section suggests some possible solutions to improve processes that could be considered by sites. 3.7.1 Engagement with industry to standardised GCP requirements

Some industry sponsors have recognised the burden being placed on clinical trial sites if they require their own GCP training course to be completed prior to their trial starting. For example some clinical trials sponsors are TransCelerate Member Companies, meaning they have signed up to the mutual recognition program for ICH E6 GCP Training. However, there is still a considerable number of sponsors that need to be convinced to accepting other GCP training courses completed within a defined period or to sign up as a TransCelerate Member Company. The most practical solution would be for either state/territory health departments or a national body (e.g. NHMRC) working with sponsors to encourage more sponsors to become TransCelerate Member Companies. This would mean clinical trials staff would only need to ensure that their GCP training certificate should be dated within 3 years of the start of a new study at the site and that investigators are

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not required to retake GCP training during study (unless required by local regulation or at the discretion of the sponsor). If all, or as many as possible sponsors, signed up to this, then this would result in a reduction of time in which clinical trials staff spend on regularly repeating unnecessary courses and reduce the need for computer access which is reportedly limited. 3.7.2 Investment in IT infrastructure available for clinical trials

Without doubt one of the most common complaints, regardless of which public hospital was visited and/or department, related to issues with the available IT infrastructure. The issues raised in regards to the IT infrastructure ranged from the lack of computer access, slow and poor quality of speed of internet, to processes required to integrate sponsors software. Problems cited included:

Lack of access to computers means delays in the completion of online training, data entry and other clinical trial reporting requirements.

Slow internet speeds means that time spent on online training, eCRF data entry, and so on is greatly increased. Quite often the online training is being undertaken offsite and out-of-hours by clinical trials staff (e.g. at home) where the internet speed is better.

Computers are a relatively inexpensive resource and it is important, from an efficiency perspective, that clinical trials staff have adequate access to computers. Sponsors are increasingly going digital for many aspects of managing a clinical trials (e.g. from required online training to electronic transfer of results to data entry and quality assurance of data). A simple audit of computer access would identify where there are issues. However funding will be required to increase the number of computers and provide the required support. With regard to internet speed, investigation into why public hospitals have insufficient internet speeds is warranted. Slow speed and poor quality internet was a constant complaint by all sites and, as most of them were metropolitan sites, the problem does not seem to relate to the unavailability of suitable services. Ensuring that all computers can obtain the necessary internet speed and computer access is sufficient would result in immediate efficiency gains at most clinical trial sites. 3.7.3 Standardisation of eCRF software platforms

Sites reported vast difference in the ease of use and speed of various eCRF platforms. Some investigation work is required to understand why different eCRF platforms perform differently (i.e. some less efficient than others) given the known IT issues across all sites. Identifying what eCRF features and/or software specifications enable certain platforms to be more efficient would be beneficial even if the IT issues (discussed under section 3.6.2) are not resolvable. Work could then commence on engaging with clinical trials sponsors to either standardise the applications used to one or two platforms, or ensuring certain specifications are met to warrant that their preferred platforms can be as efficient as possible within each clinical trial site. Either of these solutions would result in efficiency gains at most clinical trial sites. 3.7.4 Facilitate integration of clinical trials in public hospital infrastructure

Departments involved in clinical trials in public hospitals operate as solo entities. They often negotiate their own contracts and budgets, then manage their own budgets (including tracking costs and invoicing suppliers, sponsors etc.), recruit their own staff, archive their own clinical trials records, and so on. Not only do they often work in isolation from the larger business in which they sit (e.g. a public hospital), they also often work in isolation from other departments involved in similar work (albeit in a different clinical speciality). This segmentation of clinical trials units within a hospital results in inefficiencies in each hospital involved in a clinical trial as there is no leveraging of learnings, skills or resources. It is our view that hospital managers would be able to identify various efficiencies by understanding the duplication of effort by various departments being involved in clinical trials and struggling with the same

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activities. It is important that as many departments across Australian public hospitals as possible are able to offer clinical trials, as sometimes it is the best and only treatment available to their patients. In order to maintain or improve the efficiency of conducting clinical trials, it is important to look at leveraging the skills and resources already available within hospitals, and providing a forum for sharing of learnings and training would result in substantive efficiency improvement with little investment. 3.7.5 Costing and accounting for clinical trials funds

Gaining the support of finance departments within hospitals is vital to hospitals and departments within hospitals having access to more data that can be used to identify which clinical trials they lose money on, which are cost neutral or which they make profit on. Such information could be used in the feasibility assessment process, not only to support the work up of clinical trials budgets, but also to help departments to assess the viability of proposed budgets offered by sponsors. A suggested action for hospitals is to organise a series of meetings where CTC/M, PIs and finance personnel meet to discuss the various aspects of clinical trials, and develop an understanding of where the finance department can use their expertise to assist in improving the efficiency of conducting clinical trials. CTC/M and PIs sharing the tasks they undertake in the finance space and explaining theirs and sponsor’s requirements would enable finance personnel to establish processes that may involve:

initial notification from governance office (or CTM/C) that a clinical trial is about to begin and includes information on the budget, which triggers finance to set up the required cost centre structure, agreed dates for invoicing and so on;

finance advises all hospital departments involved in the clinical trial of the cost centre information so all invoices (including those generated by supporting departments) quote the number;

monthly or quarterly reports with prior information agreed about each specific clinical trial is generated by finance and provided to CTM/C and/or PI for review;

CTM/C uses the information in the reports to meet any reporting requirements; at the end of clinical trial, the finance department generates a profit and loss report and provides it

to the CTM/C and/or PI for review; annual reports that show profit and loss of all clinical trials within each department and across

departments (and compare different sponsors) are generated and provided to all CTM/Cs and presented at an annual meeting of clinical trials staff.

This process will assist hospital departments to share learnings and experiences that will inform future feasibility assessments about conducting certain types of clinical trials. It will also assist in the engagement of the finance department to better support clinical trials throughout the hospital.

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4 Site Close-Out

Site close-out of a clinical trial involves all activities associated with the close-out visit, archiving of clinical trial, and drug and biospecimen destruction. This Chapter describes the key variations identified in undertaking the site close-out processes, identifies inefficiencies and suggests possible solutions. 4.1 ARCHIVING OF CLINICAL TRIAL RECORDS

At the conclusion of a clinical trial it is necessary for the clinical trial records be collated, put into archive boxes, and for each box to be appropriately and clearly labelled. This task is largely completed by either the CTM/C (or sometimes by administrative staff within the clinical trials area) or the sponsor themselves. The boxed clinical trials records were then generally sent to an offsite storage provider or to the sponsor, as there was generally insufficient space for storage on site. F22: CTM/C are the personnel involved in the archiving of clinical trials records at close-out. 4.2 SUGGESTED SOLUTIONS

There were very few inefficiencies identified in the close-out phase of a clinical trial, except in the archiving of clinical trials records. This is largely an administrative task being undertaken by each CTM/C in each department involved in a clinical trial. Such a task could be streamlined and undertaken by a central department within the hospital, freeing up the CTM/C to continue to work on other clinical trials.

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5 General Structure and Process Issues

This Chapter describes some more general structure and process issues related to the conduct of clinical trials that are not specific to any phase of the trial lifecycle, and suggests possible solutions. 5.1 SKILLS AND EXPERIENCE OF CTM/C

The professional discipline of the occupants of CTM/C positions varied across hospitals and within hospitals. For example, within a hospital, the oncology department clinical trials unit employs nurses whereas the haematology department employees scientists or allied health professionals in the CTM/C role. Across the hospitals, the range of professional disciplines employed in CTM/C positions included:

Clinical Nurse Specialist (CNS); Clinical Nurse Consultant (CNC); Registered Nurse (RN); Scientist (e.g. medical science graduates); and Allied health professional (e.g. pharmacist, psychologist, radiation therapist). The variation in the original training or discipline of the CTM/C incumbents does impact on their ability to undertake certain activities within clinical trials. For example, science graduates are unable to provide nursing services involved in the conduct of a clinical trial. Even though there is some variation in the work scope being undertaken by the occupants of CTM/C it was not obvious that one background was more or less efficient than another. Rather the discipline of the CTM/C position was usually a preference of the hiring department and/or available funding for the position. As CTM/C positions are not recognised by any specific award, the position is paid a salary based on their discipline award (i.e. there are different award structures for nursing, medical scientists and allied health). The most noted efficiency difference in the role of CTM/C was correlated with the years of experience in conducting clinical trials and the available support provided either within the department or by the hospital. F23: The professional discipline of the occupants of CTM/C positions varied across hospitals

and within hospitals. One background was not necessarily more or less efficient than another. The most noted efficiency difference in the role of CTM/C was correlated with the years of experience in conducting clinical trials and the available support provided either within the department or by the hospital.

5.2 ESTABLISHMENT OF CLINICAL TRIALS SUPPORT ROLES

Across the three years that HealthConsult has been involved in undertaking consultations around clinical trials, there has been a noticeable increase in the number of support roles in clinical trials units. Examples of such roles include business development managers, clinical trials research operations managers and study start-up specialists. The business development manager (or equivalent title) roles have been introduced in some hospital departments due to the increasing size of some of the clinical trials units. Some large clinical trials units employ as many as 25 FTE (typically oncology clinical trials units), whereas others are as small as 1 FTE. The size of the units is driven by the number of clinical trials, as well as the number of recruited patients. So, in the larger clinical trials units, there is a need for a business manager to oversee the operations of

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the unit, as well as to ensure that there is sufficient clinical trials work to sustain the FTE. This position is usually filled by an ex-nurse unit manager that has experience in clinical trials. It is also important to note that these larger clinical trials units usually have well established relationships with the finance department (i.e. they have worked with the finance department to ensure each clinical trial has its own cost centre and have established systems and processes for tracking expenses and funding) or they employ their own finance person to manage the finances associated with conducting clinical trials. The clinical trials/research operations manager (or equivalent title) roles are more about improving and/or growing the hospitals profile in attracting, and therefore conducting, more clinical trials. Attracting clinical trials sponsors, particularly industry sponsors, generates a revenue stream to ensure that clinical research is available within public hospitals. Being able to participate in clinical research attracts clinicians to work at the hospital, and an additional revenue source is attractive to hospital CEO/managers. Such positions are also charged with identifying areas within the hospital to streamline clinical trials activities and processes. This role is a hospital-wide position rather than specific to anyone department unlike the business development managers’ role. The study start-up specialist (or equivalent title) roles are also hospital-wide roles, and are in recognition of the need for hospitals to support their departments involved in clinical trials and improve the efficiency of managing clinical trials. Such roles exist in a number of hospitals and were accessed by departments involved in clinical trials usually in the initial phase of the clinical trials process, where potential PIs or a nurse within a department would make contact to seek assistance in the site authorisation activities (e.g. feasibility questionnaire, budget negotiation, contract review etc.). These roles appeared to be highly valued and used by departments who run few clinical trials or by those departments embarking on clinical trials for the first time. In addition to these support roles, one hospital visited in 2015 was about 18 month into establishing a centralised clinical trials research office. The office was managed by an operations manager and employed a study start-up specialist and CTCs. Our understanding of the intent of this centralised office is to:

be the first port of call when a department is assessing whether or not to be a site for a clinical trial;

streamline sponsor approaches to the hospital about involvement in clinical trials;

provide hospital departments with access to a pool of experienced CTCs;

provide back-fill for CTM/C funded by hospital departments when they are on leave;

assist departments in the site authorisation and early implementation phase of a clinical trial;

train departmental staff in clinical trials (i.e. build hospital capacity in clinical trials); and

provide office space to conduct pre-screening, screening and consent activities. Establishing the office has involved the promotion of services to the hospital departments involved in clinical trials as well as to those currently not involved. The services have been sought by smaller clinical trials units, as they have been able to efficiently access an experienced CTC (i.e. removed the need to advertise and recruit), have access to an experienced CTC in the initial phases of establishing a clinical trial working with their less experienced staff; have access to clinical trials costing templates and support in working up clinical trials budgets, etc. However there has been limited success in trying to engage the larger clinical trials units (e.g. oncology, haematology etc.) to participate. Also, the centralised office was talking about having a more sustainable model which would involve charging departments for access to the services offered, including charging for access to the office space. This practice would inevitably result in clinical trials units on-charging the sponsors, however whether this model is more efficient and less expensive than a decentralised alternative would need investigation. It definitely provides an interface in the hospital for leveraging learnings and developing potential multiple-use resources, however if the larger units are unwilling to participate then there will still be replication of activities and loss of learning from very experienced units.

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F24: Hospitals or clinical trials units within hospitals are creating support role positions to assist in efficiency gains in conducting clinical trials. No one model has been investigated as to whether they actually improve efficiency. However as these models contain features of some of our proposed solutions, further investigation could lead to more insights into which of these features, and in what combination, are likely to produce the most efficient model for conducting clinical trials in Australian public hospitals.

5.3 USE OF CONTRACT RESEARCH ORGANISATIONS

Sites reported that the use of CROs by pharmaceutical, biotechnology, and medical device industry sponsors is becoming more common. Most sites reported that conducting clinical trials is less efficient if they are working with a CRO, as opposed to directly with the trial sponsor. Examples of how this loss of efficiency manifests itself included:

the need to complete feasibility questionnaires for clinical trials from multiple CROs bidding for work from trial sponsor (as raised in section 2.1.1);

budget negotiation is more time consuming if a CRO is involved, as if they misunderstood the site’s questions or if the site requires clarity around a question raised by the trial sponsor, there is additional liaison time with the CRO and lag time in awaiting for a response (as raised in section 2.1.3);

the experience of the staff at CROs was reported to be low which meant that site staff feel like they are providing training during the monitoring visits which significantly increased the time sites were required to participate in monitoring visits; and

turnover of staff at CROs was reported to be high so time incurred by hospitals bringing the new CRO monitor up to speed at the monitoring visits was increased.

The advantage of industry sponsors conducting international trials using CROs is obvious as it provides them with access to on the ground resources in locations where they are not present. However, as two departments mentioned setting their fees higher when CROs are involved, industry sponsors may need a mechanism to ensure their costs are not escalating due to this factor alone. F25: Most sites reported that conducting clinical trials is less efficient if they are working with

a CRO, as opposed to directly with the trial sponsor. This has led some departments to set higher fees when CROs are involved.

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6 Summary

This Chapter draws on the suggested solutions in the previous Chapters to identify key enablers to improving the efficiency of conducting clinical trials in public hospitals across Australia. 6.1 INVESTMENT IN INFORMATION TECHNOLOGY

Limitations in technology available at clinical trials sites was a consistent theme that emerged from all hospitals and departments consulted. These technology limitations impact on many activities in each key stage of the clinical trial lifecycle. Addressing the limitations would result in immediate and significant improvements in the efficiency of conducting clinical trials in public hospitals, by reducing the time that clinical trial staff need to undertake key activities. It is recognised that, in order to resolve the technology limitations in hospitals, funding will be needed to increase the number of computers available to clinical trial staff, to improve the quality and speed of the internet, and to encourage sponsors only to use eCRF platforms that are efficient. There may be barriers to achieving these changes (e.g. limited funding or organisation-wide IT policies and/or standards), but increasing the IT resources available to clinical trials staff would certainly yield benefits. Improving the availability and quality of clinical databases is more challenging and resource consumptive. However, given the increasing complexity of the exclusion and inclusion criteria of clinical trials protocols and the desire by industry sponsors for sites to provide more accurate estimates of potential accrual numbers, there is a need to have easily accessible good quality data. Investing in processes that enables electronic access to these data will also result in efficiency gains in clinical trials sites. 6.2 BETTER USE OF SKILLS IN CENTRALISED DEPARTMENTS

The work undertaken by HealthConsult over the last three years has identified different practices being undertaken by the various departments within hospitals involved in conducting clinical trials. Some of the practices are quite evolved due to the units having many years of experience. Other practices (typically in small or new clinical trials departments) are undeveloped, and do not leverage the existing infrastructure available within the hospitals. Most clinical trials units operate as silos, not wanting or able to leverage off existing infrastructure available within a public hospital structure. For example, most finance departments consulted at the sites were not engaged in, and sometimes not aware of, clinical trial activity occurring in their hospitals. Yet most CTM/Cs reported difficulties with costing clinical trials, managing clinical trials budgets, issuing invoices to sponsors and tracking payments. Clinical trials units and finance departments could work more closely together to reduce the pressure on clinical trials staff (i.e. by providing them with support in undertaking financial management related tasks). Such collaboration would also enable the capture of better data around clinical trials costs that could inform feasibility determinations of future clinical trials. Similar opportunities exist with respect to involving the human resources department in processes relating to recruiting clinical trials staff.

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6.3 STRUCTURED PROCESSES FOR SHARING LEARNINGS AND RESOURCES

The silo approach apparent in clinical trials departments/units in public hospitals ultimately leads to replicating the same processes and developing the same (or similar) resources. Although some (very few) sites have identified the silo approach to be inefficient and have implemented various roles to try and address this, there is still considerable opportunity. Most sites have at least one department (usually either haematology and/or oncology) that is of a significant size and has extensive experience in conducting clinical trials. Identifying these units and ensuring that whatever engagement strategy is implemented at the site includes these units will be the best way to ensure success by leveraging off already available knowledge and experience. However in order for such work to begin at sites, there needs to be a forum by which clinical trials departments within the same hospital, in the same state/territory and nationally come together to discuss the common processes and resources so sharing can begin. 6.4 STREAMLINED SITE-SPECIFIC ASSESSMENT PROCESS

Although most sites reported that the SSA process was relatively straight forward if CTM/Cs were experienced in the process, there are various aspects of the required SSA supporting documentation which, if kept centralised and current, would result in efficiencies even for the experienced CTM/Cs. For example, if there was a central repository within hospitals with copies of current curriculum vitae of investigators, insurance cover/indemnification and accreditation certification. In order for this to occur, there would need to be:

a centralised directory where such documents could be stored;

personnel designated to keeping such directories current; and

promotion to all departments about such a resource. In addition, a number of sites reported overlap between ethics and governance processes and in the requirement to provide documentation proving that standard of care interventions included in a clinical trial protocol were within safe limits (i.e. biosafety and/or radiation safety). In our view, it would be beneficial to remove any duplication between the HREC and SSA process. In order to identify the areas of overlap, both processes would need to be process mapped. Some of this work has already been done at a high level by NHMRC and by IHPA. However detailed assessment of the required documentation for both processes, as well as the personnel involved in each step needs to be more closely investigated to identify areas, if any, which can be delegated to either the (1) lead site only; (2) one site within each state/territory; (3) one site within each LHD (or equivalent); or (4) all sites. The benefits to streamlining the SSA process would result in efficiency gains by all clinical trials sites involved in a given clinical trial. Specifically it would result in a reduction in time spent by the clinical trials unit (mainly the CTM/C) in gathering all the documentation for the SSA, reduction in governance office and ethics office staff in both reviewing the same documentation; and potentially also a reduction in time spent by HREC members not having to review any duplicative documentation which may be better suited for review by the governance office staff. 6.5 STREAMLINED TRAINING

There is already work in progress on streamlining GCP training through TransCelerate BioPharma Inc.. However, as most sites continue to complain on having to repeatedly undertake the GCP training for certain companies, then there is scope for further improvement. The most practical solution to ensuring that sites are not unnecessarily undertaking GCP training is for a national body (e.g. NHMRC) or each state/territory health department to engage with sponsors to encourage more of them to become TransCelerate Member Companies. Investigating the reasons why some industry sponsors have not signed up to become TransCelerate Member Companies would be important. For example, if it is

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because there is a cost associated with becoming a TransCelerate Member Company, which is prohibitive for some sponsors, other options such as encouraging these sponsors to accept a list of “approved” courses may be sufficient to achieve a similar outcome. The benefits to more or all sponsors being TransCelerate Member Companies (or not requiring only their own approved GCP course to be completed) would result in a reduction of the amount of time in which clinical trials staff spend on regularly repeating unnecessary courses and this would also reduce the need for computer access. 6.6 CENTRALISED ORGANISATIONAL MODELS USING SPECIALIST POSITIONS

A number of sites have implemented either specialised clinical trials positions aimed at promoting uptake of clinical trials and the efficiency in which they are conducted. Some have developed centralised teams within the hospital which are staffed to support the conduct of clinical trials within their organisation from the start of site authorisation activities to the end of close-out activities. Although both models have some features of those we have suggested in this paper, none are the complete package and none have been entirely taken up by every clinical trial unit within the host organisation. It would be beneficial to conduct further investigation into these models so that their organisational structure (e.g. including the costs of establishing and maintaining such a structure) as well as the pros and cons of each model can be documented and shared. The learnings of such a process would be very informative to sites who have yet to embark, but are contemplating, implementing such initiatives. Our work conducted to date has not gathered sufficient evidence to know which model is more efficient. However, unless centralised hospital departments are fully utilised and IT infrastructure improved, neither of the two models already implemented are able to deliver on all the efficiency gains suggested in this paper. 6.7 DEVELOPMENT OF CLINICAL TRIALS MANAGEMENT PLANS

Although there is national work being done to improve the efficiency and transparency of conducting clinical trials in Australia, there is a lack of planning and transparency at individual hospital sites as to:

what departments are involved in conducting clinical trials;

personnel involved in, or experienced in conducting clinical trials;

processes and resources required and available in conducting clinical trials; and

current clinical trials on offer at each site by department. This gap results in departments embarking on conducting clinical trials for the first time, or those involved infrequently in conducting clinical trials, undertaking activities already well established by other departments, unbeknown to them. In our view, it would be beneficial if public hospitals involved in clinical trials were encouraged to develop clinical trials hospital management plans. It would be important that, at a minimum, the larger clinical trials units were involved in the development of such plans and that all clinical trials units in a hospital endorse and sign off on the plan (this would require CEO/hospital management support). In order to assist in the sharing of learnings and resources across sites (i.e. State/Territory wide and/or nationally), development of such a plan would benefit from a leadership body (e.g. state/territory health department or national body like NHMRC) providing hospitals will a standardised ‘clinical trials hospital management plan’ template that assists in their development (i.e. describes the suggested meetings to be had, the information to be sought (i.e. including a gap analysis by department), includes a template for an action plan with nominated personnel/department charged with implementing each item). A forum could then be established where completed plan are shared (i.e. across the LHD (or equivalent) or state/territory or nationally) to identify which activities/actions are more efficiently undertaken by a

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leadership body (e.g. LHD or state/territory health department or NHMRC) and the agreed ‘best practice” processes and tools are identified. All processes and tools could also be shared through a state/territory-wide or national portal and actively promoted so that replication of such processes/tools is prevented or at least reduced. 6.8 TRANSPARENT RESEARCH INFRASTRUCTURE FUNDING

In addition to pursuing the identified opportunities, there is also a need to provide more transparency in the funding of clinical research in the public hospital system. Research funding, particularly the funding of the organisational capacity in hospitals that makes doing clinical trials feasible, has always been difficult to identify. For some purposes, guesstimates are made by using what is normally an arbitrary (i.e. not well-tested formula) that expresses research funding as a percentage of total funding. But, in reality, as public hospitals have come under increasing pressure to balance budgets in the face of increasing demand, there is a widely held view that the proportion of the hospital’s operating budget that supports clinical research has diminished very considerably. As a consequence, public hospitals, in their quest to ensure that clinical research continues to be available at their organisation, have sought to identify other methods of funding. This quest has resulted in the cross-subsidisation of non-sponsor funded clinical research by funds derived from industry sponsored clinical trials. In particular, industry sponsors believe that the fee increases relating to clinical trials in Australia are, at least partly, due to the fees being used to cross-subsidise poorly funded (e.g. collaborative sponsored trials) or non-funded (e.g. investigator initiated) clinical trials. That said, all stakeholders involved (including industry), want to see good quality clinical trials available to patients in Australia. The Federal Government’s current policies that emphasise health and medical research (including the Medical Research Future Fund (MRFF)) may translate to more funding available in public hospitals for clinical research. That outcome could provide more funding for investigator initiated trials, thereby allowing public hospitals to set their clinical trials fees closer to actual cost for industry sponsored trials. But, if fees are set at levels noticeably greater than costs, then industry sponsors are likely to demand outcomes based payment models, which will put more pressure on the already struggling clinical trials infrastructure and staff. This move will likely result in further increases in fees by public hospital clinical trials sites, which might mean fewer good quality clinical trials being available to Australians. The best solution is to make research funding in public hospitals transparent, whatever the source of funds.

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