Managing multi-site clinical trials Belinda Fazekas, Linda Devilee - - PowerPoint PPT Presentation
Managing multi-site clinical trials Belinda Fazekas, Linda Devilee Flinders University receives funding for PaCCSC from the Australian Government Department of Prepared for: CPC Research Colloquium 2015 Health and Ageing under the National
Prepared for: CPC Research Colloquium 2015
Flinders University receives funding for PaCCSC from the Australian Government Department of Health and Ageing under the National Palliative Care Program.
What is PaCCSC? Phase III clinical trials conducted by PaCCSC The clinical trial lifecycle
– Pre-study – Recruitment – Completion
Recap Supporting multi-site studies in palliative care
The Palliative Care Clinical Studies Collaborative (PaCCSC) is a national research network that aims to: – Generate high quality research evidence to support the use of medicines and other interventions at the end of life to better manage or alleviate symptoms in patients such as: pain; confusion; breathlessness; appetite; and gastrointestinal problems including nausea; bowel
– Build capacity within the health workforce in the conduct of high quality clinical research in patients nearing the end of life and the translation of research results into clinical practice.
Members
Governance Structure
– Management Advisory Board – Scientific Committee – Data and Safety Monitoring Committee – Trials Management Committee
PaCCSC Recruiting Sites across the country
Central Coordinating Office in Adelaide
Flinders University
St Vincent’s Hospital/Centre for Palliative Care, Victoria The Royal Melbourne Hospital, Victoria The Austin Hospital, Victoria Barwon Health, Geelong, Victoria Mater Health Services, Queensland The Prince Charles Hospital, Queensland St Vincent’s Private Hospital, Queensland Nambour Hospital, Queensland Southern Adelaide Palliative Services, South Australia Lyell McEwin Hospital, South Australia Braeside Hospital, New South Wales Calvary Mater Newcastle, New South Wales Sacred Heart Hospice, New South Wales Calvary Health Care, Kogarah, New South Wales Greenwich Hospital, New South Wales Westmead Hospital, New South Wales John Hunter Hospital, New South Wales Liverpool Hospital, New South Wales Concord Hospital, New South Wales Ballarat Health Service, Victoria Hollywood Hospital/Curtin University, Western Australia St John of God Hospitals, Western Australia The Alfred Hospital, Victoria
Year 2 Year 3 Year 1
New idea Protocol development Sponsor Peer/ scientific review Funding
Pre Study
Trial Governance Agreements Site selection Investigation al Product Data Management SOPs Regulatory Ethics/ governance Budget Equipment/ licences Site start up
Year 9 Year 10 Years 4-8
Recruitment Data management Protocol amendments Site payments Disseminatio n plan
Recruitment
Reach sample size Data management Finalise SAP Undertake analysis Draft publication Clinical study report
Completion
Disseminatio n activities Study closure HREC final reporting
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
The light bulb moment!
Where does the idea come from?
How do I turn my new idea into a research reality?
Where do I start?
Who do I need to convince?
Where do I get support to progress the idea?
Who do I want on my team?
What expertise might I need to assist me?
PaCCSC Standard Operating Procedure (SOP) to support new idea development
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
What expertise do I need to turn this idea into a reality
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
What will each individual bring to the study; impact factor; clinical expertise; recruiting site; have they been involved before; who do they know – networks are vital to success
What does a protocol look like
– Templates, other examples
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
Where can I get assistance with the writing process
– Some template sections don’t make sense
Is what I’m trying to do in this study achievable
– Focus – Clear limits
Keeping track of changes (version control)
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
What does a Sponsor do?
– Quality assurance and quality control – Medical expertise, safety reporting, – Trial design – Trial management, data handling and record keeping – Investigator selection and allocation of responsibilities – Compensation to participants and investigators – Regulatory (CTN) and confirmation by the HREC – Investigational product, manufacturing, packaging, supply – Monitoring and audit
Who is the most appropriate sponsor for my study?
– University; Hospital; Pharmaceutical companies; biotech
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
What is peer/scientific review?
How does this review benefit my study?
– Expertise in study design and methodology – Scientific rigour – Lessons learned – Logistically successful – Implementation issues
If the average length of a CT is 10 years the protocol needs to be right from the start
Who can do this?
– Scientific Advisory Committee – Independent review x 2 (at least)
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
Year 1
New idea Protocol development Sponsor Peer Scientific review Funding
Pre Study
How much is this going to cost?
Where can I source funds?
Who will hold the funding – remember the Sponsor is primarily responsible for funding
Develop a plan – if one grant fails where to next?
Prepare submissions – expect rejection
Will the study be stalled until funding is secured?
Can the study be conducted differently, piloted initially with limited funds to gain data to support a larger scale funding application?
Have I got the right team to attract funding?
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Who needs to be involved in the governance of the trial
Is there a structure already in place that you can tap into
What committees need to be developed for what purpose
What meetings need to be held
How often should they meet
What needs to be reported
How will specialist items such as safety reporting be reported during the trial
What decisions are made where
How does the study report to the Sponsor, to the participating sites, to the funding bodies
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
What agreements/contracts are needed, who with and what for?
Funding agreement – which institution is best placed to be the lead for the study = SPONSOR or ???
Do we need Research Collaboration Agreements or Multi- Institutional Agreements put in place; with whom; will there be funding exchanged
Clinical Trial Research Agreements – Medicines Australia standard template
– Are any changes required – Will these changes stall the review and signature process – Is the funding body the Sponsor
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Which sites see the patients we want to recruit to this study
What information would be helpful for decision making about what sites to chose
What previous success has the site had with recruitment to
What are any known risks at the site/s
What other infrastructure at the site is in place
Staffing – is the Site Investigator interested in the trial, do they have a research team to support their involvement
How many sites will the study need to reach the sample size in a reasonable timeframe
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Consider site feasibility assessments
– Patient population – Likely referral numbers – Current research experience – Clinical interest – Infrastructure
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Investigational product
– Randomisation process – Blinding and manufacture – Presentation and packaging
– Stock control
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Data management
– CRFs
fields, data entry
– Trial master file needs to be set up
– Monitoring plan
All steps of the research process are correctly
– Paper trail – Auditable – Reproducible
These steps involve:
Pre clinical research Protocol Investigator brochure Case Report Forms Data base Clinical trial results Registration (new drug) New indication/ population Use in clinical practice Good clinical practice
Year 2
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Detailed written instructions to achieve uniformity of the performance of a specific function (ICH GCP).
Provides a written document that describes a specific activity
– Expected to be followed – Allows scrutiny by others of the conduct of the study – Procedures undertaken the same way across the whole study. – Enables site documents to refer to for assistance – Used as standard for monitoring
Why are SOP’s needed?
– Consistency across sites – Compliant with ICH GCP
What SOP’s are needed
– Can I use those from others – What happens if I don’t have any
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Sample contents page of PaCCSC SOPs.
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Trial Registration
– A trial must be registered prior to first recruitment – www.anzctr.org.au is an online registry of clinical trials being undertaken in Aust & NZ,
Clinical Trial Research Agreements (CTRA)
– Medicines Australia have standard template agreements for trials – www.medicinesaustralia.com.au
Clinical Trial Notification with the Therapeutic Goods Administration
– https://www.tga.gov.au/
Insurance and indemnity
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Ethics/governance
– NEAF
– HREC selection
– SSAs
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Ethics/governance
– Watch for traps
control is important
– Central coordination of the process by the Sponsor
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
Working financial model
Income in, expenditure out
How will you subsidise sites for recruitment – per participant payment model, incentive payments, data payments
What other costs
– Ethics, lead site – IP/placebo, supply, packaging, distribution, pharmacy – Data related – RDMS, entry, storage, checking, – Human resourcing/project officer etc – Equipment – Site visits – initiation, monitoring, closure – Human resources – Teleconferencing
Year 2
Pre Study
SOPs Regulatory Ethics Governance Budget Equipment Licences
What equipment is needed for the study?
Where can I source the equipment, what is the cost, does it need testing, calibrating, maintenance, will staff need to be trained in the use of the equipment, does the equipment require insuring
What assessment tools and licences are written into the protocol?
Where do I go to seek permission or buy licences to use the tools, how much will it cost, is the cost per site, do the licences expire, do original only versions need to be used
Installation issues and firewalls
Year 3
Site Start up
Pre Study
Let the fun begin!
The list is endless:
– CRF finalisation and folder development – Investigator folders – Pharmacy procedures and folder – Regulatory sign-off – Site initiation and training – Data base access – Arrange delivery of folders, equipment, IP etc
Year 3
Site Start up
Pre Study
Data requirements and management
– Data entry and data quality issues – Trial master files – Site master files – Storage
Year 3
Site Start up
Pre Study
Start thinking about the next study!
Year 3
Site Start up
Pre Study
Year 2 Year 3 Year 1
New idea Protocol development Sponsor Peer/scientific review Funding
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management SOPs Regulatory Ethics/ governance Budget Equipment/ licences Site start up
Year 9 Year 10 Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Reach sample size Data management Finalise SAP Undertake analysis Draft publication Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
The hard yards
Keeping things going
Momentum
Demoralised staff
– Recruitment is hard work
Complacency
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Recruitment
– New sites – Training – Feedback – Monitoring recruitment – Staying on track
Procedures to prevent leakage
– Are consent procedures changing over time – Are some clinical areas being excluded – Impact of staff changes
Procedures for tracking and reporting recruitment
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Data management
– Safety
– How do off-site events get communicated to the other sites – What is reported to HREC – Overview of DSMC
– safety assessment – recruitment checking – data quality issues
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Data management
– Progress/KPIs
Is recruitment as expected
What will you do if the projection is not reached
Do any strategies result in a change in recruitment
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Example strategies
– Calculator to determine dose changes in complex study – Training around consent wording, with example words to use – Protocol changes to improve eligibility – Discussion around referral sources
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Data management
– Monitoring
– Data checking
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Who manages the data
– Is the data being collected and checked – Is the data being looked at – What quality issues are presenting – Can this be changed
– Consider logging the data entry and errors
programme
Patient ID Form ID / Process Date Received Date Entered Entered By Checked Date Checked Checked By Errors Percentage Of Errors Errors Resolved Date Resolution Checked Resolution Checked By
08/26/002/402 Randomisation Fax 19/01/2015 20/01/2015 LFG 08/26/002/402 Monitored 12/05/2015 3 Yes 26/05/2015 BF 08/26/002/402 Pre-screen 08/26/002/402 Eligibility 13/03/2015 16/03/2015 MK Yes 18/03/2015 AH
13/03/2015 10/02/2015 MK Yes 16/03/2015 MK
13/03/2015 10/02/2015 DC Yes 16/03/2015 MK
08/26/002/402 Cessation 13/03/2015 10/02/2015 DC Yes 16/03/2015 MK
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
When and why would you amend the protocol?
Implications of protocol amendments
– HREC, SSA – Training and education – Data changes – what happens now affects what happens at the end, maintaining data integrity
Budgetary implications
Delays to recruitment
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
What model do you use to reimburse the recruiting sites for their study accrual?
Payments linked to performance
– Per participant payments – Lead site payments (pa) – Carrot payments
Management of payments
– Good record keeping – Linked to data logs – no data no payment
Reporting back to funding bodies
Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Develop strategies to ensure that key findings of your study are disseminated to key stakeholder groups
Do you need to liaise with pharmaceutical companies to ensure the results are relevant and available to enable submissions to the TGA and PBAC
All trial results, regardless of the outcome (positive/negative) should be subjected to peer review and many funding bodies now make this a requirement
How do you make your study findings publicly available in an efficient and timely manner – data analysis can take months/years
How do you make study findings available to the clinical sector and change practice
What secondary analyses will be done and why?
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
The end is in sight!
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Samples size reached
– Protocol violations – Even distribution across arms – Final numbers checked – Study closed to recruitment
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Data management
– Data entry complete – All data checked and corrected
– Final download of dataset
– Problems with the CRFs show up here!
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Finalise SAP
– Check against protocol – Complete template tables
Complexity varies
– Can help to focus the analysis and the way the results are displayed – Ensures that analysis is decided BEFORE the study is unblinded – Prevents mining for results
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Undertake analysis
– Unblinding – Patient flow (CONSORT)
– Demographics
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Consort diagram
– Have you lost a patient
Assessed as eligible n=194 Not randomized n=7 Did not consent = 2 Changed mind = 2 Clinical request = 1 Hospital transfer = 1 Study medication not available = 1 Randomised n=187 Allocated to ketamine n=93 Allocated to placebo n=92 Received ketamine n=91 Received placebo n=90 Did not receive ketamine n=2 Withdrew consent n=1 Changed therapy n=1 Did not receive placebo n=2 Clinical request = 1 Patient request = 1 Completed ketamine n=75 Completed placebo n=75 Discontinued ketamine n=16 Clinical deterioration = 7 Patient/clinical request = 5 Change in therapy = 4 Discontinued placebo n=15 Clinical deterioration = 6 Patient/clinical request = 5 Change in therapy = 4 Completed 5 days ketamine n=39 Completed 5 days placebo n=35 Treatment failure (24 hours at maximal dose) n=38 Treatment failure (discontinued due to toxicity) n=2 Treatment failure (24 hours at maximal dose) n=19 Treatment failure (discontinued due to toxicity) n=17 Deleted from analysis n=2
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Undertake analysis
– Secondary outcomes – What do the results mean
– How to present the results
tables, diagrams etc
Year 9
Reach sample size Data management Finalise SAP Undertake analysis Draft publication
Completion
Draft publication
– Authorship – Version control – What is the scope of the publication
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
The light at the end is shining!
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Final reporting to HREC
– May be multiple committees – Site recruitment rates – Adverse events – Include results
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Populate SAP and complete clinical study report
– ICH GCP template is 32 pages – Contains everything
– How was the study run, are there any flaws – Publications along the way
Who takes ownership of this report?
Is a results publication enough?
Octreotide for secretions in bowel obstruction
– Inpatient – 3 days of sc infusion – July 2007– October 2015
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Dissemination activities
– How to get the results known – Involve the recruiting sites in the process – How to measure inclusion in clinical practice
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Study closure
– Final reports – Pharmacy drug destruction – Archiving of study materials
close
what if people leave, consider computing changes
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Study closure
– Final reports – Pharmacy drug destruction – Archiving of study materials
close
what if people leave, consider computing changes
Done!
Year 10
Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Year 2 Year 3 Year 1
New idea Protocol development Sponsor Peer/scientific review Funding
Pre Study
Trial Governance Agreements Site selection Investigational Product Data Management SOPs Regulatory Ethics/ governance Budget Equipment/ licences Site start up
Year 9 Year 10 Years 4-8
Recruitment Data management Protocol amendments Site payments Dissemination plan
Recruitment
Reach sample size Data management Finalise SAP Undertake analysis Draft publication Clinical study report
Completion
Dissemination activities Study closure HREC final reporting
Membership Quarterly Newsletter Annual Research Forum
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