Managing multi-site clinical trials

Transcription

1 Managing multi-site clinical trials Belinda Fazekas, Linda Devilee 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.

2 Overview 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

3 What is PaCCSC 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 obstruction; and constipation. 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.

4 Where is PaCCSC? 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

5 PaCCSC Sites 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

6 MULTI-SITE CLINICAL TRIAL LIFECYCLE

7 Clinical Trial Life Cycle Year 1 Year 2 Year 3 Years 4-8 Year 9 Year 10 New idea Trial Governance SOPs Recruitment Reach sample size HREC final reporting Protocol development Agreements Regulatory Data management Data management Clinical study report Sponsor Peer/ scientific review Funding Site selection Investigation al Product Data Management Ethics/ governance Budget Equipment/ licences Site start up Protocol amendments Site payments Disseminatio n plan Finalise SAP Undertake analysis Draft publication Disseminatio n activities Study closure Pre Study Recruitment Completion

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9 YEAR BY YEAR

10 Year one Year 1 New idea Protocol development Sponsor Peer Scientific review Funding Pre Study

11 Year 1 The New Idea Year 1 New idea Protocol development Sponsor Peer Scientific review 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 Funding Pre Study

12 Year 1 Development of the Protocol Year 1 New idea Protocol development What expertise do I need to turn this idea into a reality Sponsor Peer Scientific review Funding Pre Study

13 Year 1 Development of the Protocol Year 1 New idea Protocol development 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 Sponsor Peer Scientific review Funding Pre Study

14 Year 1 Development of the Protocol Year 1 New idea Protocol development Sponsor Peer Scientific review Funding Pre Study

15 Year 1 Development of the Protocol Year 1 New idea Protocol development 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) Sponsor Peer Scientific review Funding Pre Study

16 Year 1 - Sponsor Year 1 New idea Protocol development Sponsor Peer Scientific review 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 Funding Pre Study

17 Year 1 Peer/Scientific Review of the Protocol Year 1 New idea Protocol development Sponsor Peer Scientific review Funding 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) Pre Study

18 Year 1 - Funding Year 1 New idea Protocol development Sponsor Peer Scientific review Funding Pre Study

19 Year 1 - Funding Year 1 New idea Protocol development Sponsor Peer Scientific review 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? Funding Pre Study

20 Year Two Year 2 Trial Governance Agreements Site selection Investigational Product Data Management Pre Study

21 Year 2 Trial Governance Trial Governance Agreements Site selection Investigational Product Data Management Year 2 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 Pre Study

22 Year 2 - Agreements Trial Governance Agreements Site selection Investigational Product Data Management Year 2 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 Pre Study

23 Year 2 Site selection Year 2 Trial Governance Agreements Site selection Investigational Product Data Management Pre Study

24 Year 2 Site selection Trial Governance Agreements Site selection Investigational Product Year 2 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 other trials 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 Data Management Pre Study

25 Year 2 Site selection Trial Governance Agreements Site selection Year 2 Consider site feasibility assessments Patient population Likely referral numbers Current research experience Clinical interest Infrastructure Office Computer Resources Investigational Product Data Management Pre Study

26 Year 2 Investigational Product Trial Governance Agreements Site selection Year 2 Investigational product Randomisation process Blinding and manufacture Presentation and packaging Expense Ease of administration Accountability issues Stock control Dispensing and returns Investigational Product Data Management Pre Study

27 Year 2 Data Management Trial Governance Agreements Site selection Investigational Product Year 2 Data management CRFs How will the data be collected, in what format, who will collect, data fields, data entry Trial master file needs to be set up Paper or electronic Easy to maintain from day 1, prevents loss of documents (ICH GCP) Version control Monitoring plan Frequency Type Personnel Elements to be monitored Data Management Pre Study

28 Trial Governance Agreements Site selection Year 2 Good Clinical Practice All steps of the research process are correctly undertaken and can be proven Paper trail Auditable Reproducible These steps involve: Pre clinical research Protocol Investigator brochure Case Report Forms Data base Investigational Product Data Management Use in clinical practice Registration (new drug) New indication/ population Clinical trial results Pre Study Good clinical practice

29 Year 2 Standard Operating Procedures Year 2 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 Pre Study

30 Year 2 SOPs Sample contents page of PaCCSC SOPs. Regulatory Ethics Governance Budget Equipment Licences Pre Study

31 Year 2 - Regulatory Year 2 SOPs Regulatory Ethics Governance Budget Equipment Licences Pre Study

32 Year 2 - Regulatory Year 2 SOPs Regulatory Ethics Governance Budget Trial Registration A trial must be registered prior to first recruitment 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 Clinical Trial Notification with the Therapeutic Goods Administration Insurance and indemnity Equipment Licences Pre Study

33 Year 2 Ethics & Governance Year 2 SOPs Regulatory Ethics Governance Budget Equipment Licences Ethics/governance NEAF Master documents Attachments Management of ownership Version control becomes important HREC selection Does the HREC selection matter Lead HREC approval listing all sites and all documents SSAs Generation Management Attachment control (Trial Master file and site files) Local RGO approval prior to site start Pre Study

34 Year 2 Ethics & Governance Year 2 SOPs Regulatory Ethics Governance Budget Ethics/governance Watch for traps Ensure approval letter lists all sites Ensure approval letter lists ALL patient documents exactly. Version control is important Ethics approval then local governance approval Central coordination of the process by the Sponsor Must maintain records of all protocol approval and amendment Must maintain records of all site approvals, amendments and reports Lead site (additional work and resourcing) Lead HREC Lead PI Reminder function to all sites to report, as per requirements etc etc Equipment Licences Pre Study

35 Year 2 - Budget Year 2 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 Pre Study

36 Year 2 - Equipment and Licences Year 2 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 Pre Study

37 Year Three Year 3 Let the fun begin! Site Start up Pre Study

38 Year 3 - Site Start Up Year 3 Site Start up 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 Pre Study

39 Year 3 Site Start Up Year 3 Data requirements and management Data entry and data quality issues Trial master files Site master files Storage Site Start up Pre Study

40 Year 3 Site Start Up Year 3 Start thinking about the next study! Site Start up Pre Study

41 The Trial is Open to Participant Recruitment Year 1 Year 2 Year 3 Years 4-8 Year 9 Year 10 New idea Trial Governance SOPs Recruitment Reach sample size HREC final reporting Protocol development Agreements Regulatory Data management Data management Clinical study report Sponsor Site selection Ethics/ governance Site start up Protocol amendments Finalise SAP Dissemination activities Peer/scientific review Investigational Product Budget Site payments Undertake analysis Study closure Funding Data Management Equipment/ licences Dissemination plan Draft publication Pre Study Recruitment Completion

42 Years 4-8 Years 4-8 Recruitment Data management Protocol amendments The hard yards Keeping things going Momentum Demoralised staff Recruitment is hard work Complacency Site payments Dissemination plan Recruitment

43 Years 4-8 Recruitment Years 4-8 Recruitment Data management Protocol amendments Site payments 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 Dissemination plan Recruitment

44 Years 4-8 Recruitment Referred Randomised % Ketamine Octreotide Risperidone Megestrol Total

45 Years 4-8 Data Management Years 4-8 Recruitment Data management Protocol amendments Site payments Dissemination plan Data management Safety Reporting and red flags How do off-site events get communicated to the other sites What is reported to HREC Overview of DSMC Reporting Assessment Outcomes Interim analysis safety assessment recruitment checking data quality issues Recruitment

46 Years 4-8 Data Management Years 4-8 Recruitment Data management Protocol amendments Site payments 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 Dissemination plan Recruitment

47 Years 4-8 Data Management Years 4-8 Recruitment Data management Protocol amendments 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 Site payments Dissemination plan Recruitment

48 Years 4-8 Data Management Years 4-8 Recruitment Data management Data management Monitoring Onsite Desktop Risk based for cause Data checking Protocol amendments Site payments Dissemination plan Recruitment

49 Years 4-8 Data Management Years 4-8 Recruitment Data management Protocol amendments Site payments 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 Further training Changes to CRFs Consider logging the data entry and errors Related to data at the end of the study Related to payments Can be a spreadsheet in excel or a functional programme Dissemination plan Recruitment

50 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/ /01/2015 LFG 08/26/002/402 Monitored 12/05/ Yes 26/05/2015 BF 08/26/002/402 Pre-screen 08/26/002/402 Eligibility 13/03/ /03/2015 MK Yes 18/03/2015 AH - 08/26/002/402 Baseline 13/03/ /02/2015 MK Yes 16/03/2015 MK - 08/26/002/402 Commenced 13/03/ /02/2015 DC Yes 16/03/2015 MK - 08/26/002/402 Mid Week Call 08/26/002/402 Cessation 13/03/ /02/2015 DC Yes 16/03/2015 MK -

51 Years 4-8 Protocol Amendments Years 4-8 Recruitment Data management Protocol amendments 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 Site payments Dissemination plan Recruitment

52 Years 4-8 Site Payments Years 4-8 Recruitment Data management Protocol amendments Site payments Dissemination plan 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 Study start up Data finalisation Study closure Management of payments Good record keeping Linked to data logs no data no payment Reporting back to funding bodies Recruitment

53 Years 4-8 Dissemination plan 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 of funding 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?

54 Year 9 Year 9 The end is in sight! Reach sample size Data management Finalise SAP Undertake analysis Draft publication Completion

55 Year 9 Sample size is reached Year 9 Reach sample size Data management Samples size reached Protocol violations Even distribution across arms Final numbers checked Study closed to recruitment Finalise SAP Undertake analysis Draft publication Completion

56 Year 9 Data Management Year 9 Reach sample size Data management Finalise SAP Data management Data entry complete All data checked and corrected Data checking procedures Audit trail of changes, how is this done Final download of dataset Version control Problems with the CRFs show up here! Undertake analysis Draft publication Completion

57 Year 9 Finalise Statistical Analysis Plan Year 9 Reach sample size Data management Finalise SAP 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 Undertake analysis Draft publication Completion

58 Year 9 Undertake Analysis Year 9 Reach sample size Data management Undertake analysis Unblinding Patient flow (CONSORT) Can every patient be accounted for Comes back to tracking throughout recruitment Demographics Finalise SAP Undertake analysis Draft publication Completion

59 Year 9 Reach sample size Year 9 Undertake Analysis Consort diagram Have you lost a patient Deleted from analysis n=2 Allocated to ketamine n=93 Assessed as eligible n=194 Randomised n=187 Allocated to placebo n=92 Not randomized n=7 Did not consent = 2 Changed mind = 2 Clinical request = 1 Hospital transfer = 1 Study medication not available = 1 Data management Did not receive ketamine n=2 Withdrew consent n=1 Changed therapy n=1 Received ketamine n=91 Received placebo n=90 Did not receive placebo n=2 Clinical request = 1 Patient request = 1 Finalise SAP Undertake analysis Discontinued ketamine n=16 Clinical deterioration = 7 Patient/clinical request = 5 Change in therapy = 4 Completed ketamine n=75 Completed placebo n=75 Discontinued placebo n=15 Clinical deterioration = 6 Patient/clinical request = 5 Change in therapy = 4 Draft publication Completion Treatment failure (24 hours at maximal dose) n=19 Treatment failure (discontinued due to toxicity) n=17 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

60 Year 9 Undertake Analysis Year 9 Reach sample size Data management Finalise SAP Undertake analysis Secondary outcomes What do the results mean In the context of this patient population In the context of the intervention or use of medication How to present the results Transformation from STATA/SPSS etc output in to meaningful tables, diagrams etc Undertake analysis Draft publication Completion

61 Year 9 Draft Publication Year 9 Reach sample size Draft publication Authorship Version control What is the scope of the publication Data management Finalise SAP Undertake analysis Draft publication Completion

62 Year 10 Year 10 The light at the end is shining! HREC final reporting Clinical study report Dissemination activities Study closure Completion

63 Year 10 HREC Final Reporting Year 10 HREC final reporting Clinical study report Final reporting to HREC May be multiple committees Site recruitment rates Adverse events Include results Dissemination activities Study closure Completion

64 Year 10 Clinical Study Report Year 10 HREC final reporting Clinical study report Dissemination activities Study closure Populate SAP and complete clinical study report ICH GCP template is 32 pages Contains everything Populated from information collected during study Access to the data base Meeting and outcomes (DSMC, protocol violations, monitoring) Allocations Descriptions of AE, SAEs and deaths How was the study run, are there any flaws Publications along the way Who takes ownership of this report? Is a results publication enough? Completion

65 Phase III studies - DoH Octreotide for secretions in bowel obstruction Inpatient 3 days of sc infusion July 2007 October 2015

66 Year 10 Dissemination Activities Year 10 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 Clinical study report Dissemination activities Study closure Completion

67 Year 10 Study Closure Year 10 HREC final reporting Clinical study report Dissemination activities Study closure Completion

68 Year 10 Study Closure Year 10 HREC final reporting Clinical study report Study closure Final reports Pharmacy drug destruction Archiving of study materials Need to ensure every site has completed the tasks required to close Where do the study files get stored, who has access, how long for, what if people leave, consider computing changes Dissemination activities Study closure Completion

69 Year 10 Study Closure Year 10 HREC final reporting Clinical study report Dissemination activities Study closure Completion

70 Year 10 Study Closure Year 10 HREC final reporting Clinical study report Dissemination activities Study closure Final reports Done! Pharmacy drug destruction Archiving of study materials Need to ensure every site has completed the tasks required to close Where do the study files get stored, who has access, how long for, what if people leave, consider computing changes Study closure Completion

71 Year 10 Study Closure Year 10 HREC final reporting Clinical study report Dissemination activities Study closure Completion

72 Overview of the clinical trial life-cycle Year 1 Year 2 Year 3 Years 4-8 Year 9 Year 10 New idea Trial Governance SOPs Recruitment Reach sample size HREC final reporting Protocol development Agreements Regulatory Data management Data management Clinical study report Sponsor Site selection Ethics/ governance Site start up Protocol amendments Finalise SAP Dissemination activities Peer/scientific review Investigational Product Budget Site payments Undertake analysis Study closure Funding Data Management Equipment/ licences Dissemination plan Draft publication Pre Study Recruitment Completion

73 Can PaCCSC assist your next study? Membership Quarterly Newsletter Annual Research Forum March 3 rd and 4 th 2016 Sydney