36 th Annual Meeting Preconference Workshop P4 Handout

Transcription

1 36 th Annual Meeting Preconference Workshop P4 Handout

2 Clinical Trial Management in Multicenter Trials: Collaborating for Success Meet Our Team Dixie Ecklund, RN, MSN, MBA Associate Director, University of Iowa Clinical Trials Statistical & Data Management Center Marianne Kearney Chase, BA Director of Research Operations, Neurological Clinical Research Institute, Massachusetts General Hospital Leigh Ann Chamberlin, RD, MEd Supervisor of Clinical Research, Cincinnati Children's Medical Center Our Team s Goals Provide you with tools and tips to achieve better harmonization of efforts to successfully implement and conduct from start to finish multicenter clinical trials from all partner perspectives. 1

3 Taking those first steps towards teamwork Creating Your Team Identify the right team members Experience, Strengths, Passion Regulatory Financial Study Material Development Data Entry Data Analysis Use central resources Define and refine roles Get to Know Your Players Build rapport, trust and confidence Begins immediately Frequent interactions Face to face and phone Regularly scheduled meetings Maximize time with collaborators Create a vision Budget time wisely It will take more time than you ever thought! 2

4 All I Really Need to Know I Learned in Kindergarten (A Guide to Leadership) - Robert Fulghum When you go out into the world, watch out for traffic, hold hands, and stick together. Imagination What Is Needed to Succeed? Brand your trial with a logo or acronym Separate Trainings for PI and Coordinator Pocket References Who to Contact Study Visit Schedule Inclusion/Exclusion Criteria Key Handouts I believe that imagination is stronger than knowledge. -Robert Fulgham Share Everything -Robert Fulgham 3

5 It doesn t matter what you say you believe - it only matters what you do. -Robert Fulgham Go Above and Beyond Educate yourself Appreciate the work of others Celebrate Successes Embrace Failures Be Prepared for the Unknown Who would have known? When Challenges Arise Freedom to challenge practices that are out of alignment or ineffective Listen even if passionate about your perspective Honest, open communication Conflict management It s business, not personal Grant Award and/or Parent contract established Protocol Synopsis finalized Schedule of Activities finalized Four Stages of a Clinical Trial Protocol and ICF finalized Sites selected Operations Manual/MOP completed CRFs finalized IRB approvals obtained Site contracts Vendor contracts Build database Finalize study drug packaging/labeling Orientation or Initiation Meeting Enroll subjects Distribution of study drug and supplies Ongoing training for sites Answer protocol questions Monitor site compliance Data management Manage Key Study Events Financial Sponsor and DSMB Communications Newsletters Payments Database Lock Data Analysis Data query process Clean/Close database Transfer database to Biostatistics Primary/ secondary analysis Submit manuscript Submit Clinical trial report Post-hoc analysis PROJECT CONCEPT STUDY START UP FIRST ENROLLED TO LAST VISIT STUDY COMPLETION 4

6 The Marathon Begins Grant Award and/or Parent contract established Protocol Synopsis finalized Schedule of Activities finalized PROJECT CONCEPT Four Stages of a Clinical Trial Protocol and ICF finalized Sites selected Operations Manual/MOP completed CRFs finalized IRB approvals obtained Site contracts Vendor contracts Build database Finalize study drug packaging/labeling Orientation / Investigator Meeting STUDY START UP FIRST ENROLLED TO LAST VISIT STUDY COMPLETION Steering Committee Others DSMB Vendors Project Team PI, PM, DM, SM, GM, OT, Biostatisticians Consultants Funding Source Medical Monitor Sites 5

7 Create Core Project Team PPI/ Co-PI Project Manager(s) Data Manager(s) Systems Manager/ Analyst Grants and Contracts Manager Study Monitors Outcome Measures Trainers Administrative Assistance Create Steering Committee: Advisory to Study Team Study design Scientific integrity of study Ethical and overall conduct of the study Safety of study subjects Review and approval of amendments Publication policy Trouble shooting Site issues Safety Monitoring Independent Medical Monitor/ Safety Monitor Data and Safety Monitoring Board Periodically review accumulated data for safety, study conduct and when appropriate, efficacy Make recommendations concerning continuation, modification, or termination of trial Responsibility to: Participants, Institutional Review Board (IRB)/ Ethics Committee (EC), Principal Investigator (PI), Financial Sponsor, Regulatory Agencies (FDA/Health Canada/EMA/other) 6

8 Site Selection How many sites will be needed to meet enrollment target within budgeted timeline? Site feasibility: Patient population Equipment Interest/ Excitement Experience and staff availability Protocol and Consent Form Development Ensure protocol contains all required elements Read protocol with a focus of collecting data required for analysis of study endpoints Is the protocol patient-friendly? Frequency of visits Time commitment per visit Prepare a model Informed Consent Form (ICF) with standard language to describe study rationale, procedures and potential risks/ benefits Data Capture System Determine what data needs to be entered into the database Use standardized terms for collecting data Common Data Elements (CDEs) Create CORE forms Demographics, Medical history, Standard outcome measures Create tools to assist sites with collection of study data (source document templates) 7

9 Vendor Selection Who will be manufacturing your Drug/ Device/ placebo? Do you need to contract with a central pharmacy to distribute your drug/placebo? Will your laboratory samples be processed locally or centrally? If ECGs are included in your study, will they be read locally or centrally? Vendor management can be challenging! Regulatory and Contracts Does your study require oversight by a regulatory agency (FDA/EMA/ Health Canada)? Will your study be reviewed by local IRB/ EC at each site or will there be central IRB/EC review? What type of a clinical trial agreement needs to be executed with each site? Request site specific regulatory documents from all sites and review for accuracy/completeness Track study metrics (time to execute contract, time to IRB approval, etc.) NINDS funded NeuroNEXT Network Expand the NINDS capability to test promising new therapies, increase efficiency of clinical trials before embarking on larger studies, and respond quickly as new opportunities arise to test promising therapies for people with neurological disorders Initiatives to improve efficiency during study start up: Master Clinical Trial Agreement Central IRB review of protocol 8

10 Develop Study Management Tools Data Management Plan How will data be reviewed throughout the study? Statistical Analysis Plan Will there be an interim analysis? Randomization Plan Will you need an Interactive Web-based Response System (IWRS)? Study Monitoring Plan Remote data review vs. on-site visits? Risk-based monitoring Develop Manuals/ Workflows Site Manual of Procedures (MOP) Site supply/re-supply Adverse Events/ Serious Adverse Events Protocol Deviations Independent Medical Monitor and/or DSMB Vendors More Hurdles Ahead! 9

11 Plan/Execute Investigator Meeting Good Clinical Practice (GCP) Scientific Rationale Overview of protocol and study procedures Statistical considerations Potential risks of study, investigational product Investigational product storage, dispensing and accountability Study monitoring and Safety monitoring Outcome measures training/ certification** Recruitment and Retention plan for the study** Contracts and payment Data Capture system Laboratory/Pharmacy and/or other vendor related items Provide Sites with Study Materials Distribute to Sites Manual of Procedures Regulatory binders Pharmacy binders Investigator s brochure Study tools (source document templates, recruitment materials, etc) Upload documents to study portal Post study on clinicaltrials.gov and other websites, as appropriate Training/Lab Kits/Supplies/Drug Plan and execute training: Site Initiation Visit EDC training Pharmacy training Outcome measures training Ship study supplies to site Ship study drug to site Trigger Central Laboratory to ship lab kits to sites 10

12 Site Activation Track site readiness to begin recruiting subjects: Site Staff regulatory documents complete Staff training complete Site IRB/ EC approval Fully executed contract Study supplies received by site Drug received by site Send confirmation letter to confirm site can begin recruiting subjects Study Start Up is Exhausting, but 11

13 Grant Award and/or Parent contract established Protocol Synopsis finalized Schedule of Activities finalized Four Stages of a Clinical Trial Protocol finalized Model ICF finalized Sites selected Operations Manual/MOP completed CRFs finalized IRB approvals obtained Site subcontracts/ payment schedule in place Finalize contracts with third party vendors (labs, ECGs etc.) Build database Finalize study drug packaging/labeling Orientation or Initiation Meeting Enroll subjects Distribution of study drug and supplies Ongoing training for sites Answer protocol questions Monitor site compliance Data management Manage Key Study Events Financial Sponsor and DSMB Communications Newsletters Payments PROJECT CONCEPT STUDY START UP FIRST ENROLLED TO LAST VISIT STUDY COMPLETION Ready to Enroll? Investigators Educate your clinic team Introduce key players Consider clinical flow and space needs Develop talking points Coordinators Print materials Practice consenting process Communicate with your sponsor It doesn t matter what you say you believe - it only matters what you do. -Robert Fulgham Be available when sites need help Go above and beyond Respond immediately Consider time zone differences Provide cell phone numbers after hours Monthly coordinator teleconferences 12

14 Enrolling the first subject Avoid waiting too long Understand recruitment flow Weekly interaction between site investigator and coordinator Pace yourself Follow Up with your team Site Retraining Visit Site Visits as Opportunities Personalized attention Clinic flow(every site functions differently) Staffing needs Data entry Study documents Questions and answers Study drug storage 13

15 Staff Turnover Monitoring Site Performance Enrollment Metrics Define in site contract Site will enroll and complete all the aspects of the trial for 17 subjects and their families (not to exceed a maximum enrollment of 675 subjects across all sites). Sites are expected to enroll subjects at a rate of 1 subject every two months. Track through Weekly Reports/Enrollment Graphs Site Probation and Termination Policy Monitoring Site Data Remote monitoring Promote data quality Prevent data entry errors Mandatory fields Data entry ranges Drop down boxes Radio buttons Skip patterns 14

16 Monitoring Site Data On Site Monitoring Visits Initial Visit Parameters After 3 subjects randomized or annually Subsequent Visits Additional 6 subjects randomized Center issues Adverse Events Missing Data Out of Window Visits Protocol Deviations Drug Accountability Enrollment Issues Monitoring Site Data Data Queries/Monthly Reports User friendly Training Point of contact Follow up to ensure data changes are made Managing Key Study Events 15

17 Managing Key Study Events Protocol Deviations Present safety concern Demonstrative impact on study integrity Others assess through quality improvement Clearly defined reporting criteria and time frame Managing Key Study Events Adverse Events Common Terminology Criteria for Adverse Events (CTCAE codes) Training Frequently used codes Role of Independent Medical Monitor Prompt Review of Serious Adverse Event AE relatedness determination Blinded monthly AE tabulation reports Sponsor Communications s Newsletters Monthly Coordinator Calls Investigator Calls In Person Meetings in conjunction with Scientific Meetings Annual Updates/Mailings DSMB Interim Analyses 16

18 Celebrate milestones Site Payments Start Up Funds Incremental Release based on deliverables Quarterly Site Payment based on visits conducted and data entry Decrease site costs (FedEx, study supplies) Avoiding burnout 17

19 Grant Award and/or Parent contract established Protocol Synopsis finalized Schedule of Activities finalized Four Stages of a Clinical Trial Protocol finalized Model ICF finalized Sites selected Operations Manual/MOP completed CRFs finalized IRB approvals obtained Site subcontracts/ payment schedule in place Finalize contracts with third party vendors (labs, ECGs etc.) Build database Finalize study drug packaging/labeling Orientation or Initiation Meeting Enroll subjects Distribution of study drug Data query process and supplies Clean/Close Ongoing training for sites database Answer protocol questions Transfer database to Biostatistics Monitor site compliance Primary/ Data management secondary analysis Manage Key Study Events Financial Sponsor and DSMB Communications Newsletters Payments Database Lock Data Analysis Submit manuscript Submit Clinical trial report Post-hoc analysis PROJECT CONCEPT STUDY START UP FIRST ENROLLED TO LAST VISIT STUDY COMPLETION Text 18

20 Planning for Close-Out Activities Communication between all collaborators on close-out procedures and timeline for data lock Work with sites to complete data entry and resolve all outstanding data queries Resolve all data queries and data issues Data freeze/data lock 19

21 Planning for Close-Out Activities How to handle missing data? Analysis programs are developed and debugged Final analysis done per Statistical Analysis Plan specified apriori Planned closed out? OR Close-out as a result of an interim analysis and DSMB decision? Close-outs due to interim analysis Closed for safety, futility, or efficacy? Early drug withdrawal visits Safety assessments Unblinding Endpoint data 20

22 Planned Close-Outs Query missing data until completed AE follow-up and resolution period Resolution of all AEs (with or without sequalae) All deviations reported and CAPAs identified Site Close-Out Visits Final on-site monitoring visit Reconciliation of files Final drug and supply accountability Sites must retain all original study records until receive notification from Sponsor Close-out letter When to close IRB? Reports Steering Committee DSMB IRB Sponsor FDA How are subjects informed of results? 21

23 Publications Lead authors determined through Publication Policy In order to be published, phase II and III studies must have been registered on clinicaltrials.gov CONSORT requirements Publication plan (pre-close out) Methodology paper published in start-up phase (referenced in results paper) Baseline paper published after all subjects enrolled and randomized (referenced in results paper) 22

24 Publication plan (post-close out) Primary results manuscript Authorship Timelines Secondary analyses Data access Authorship Timelines Post-hoc analyses Data access Authorship Timelines FDA submissions If conducted under an IND, a final Clinical Study Report (CSR) must be submitted to FDA 23

25 Data Sharing (Results) Requirement for NIH-funded studies Need to consider sharing with Participants, Sponsor, Community Media releases Conflicts of Interest Submit results to clinicaltrials.gov within 12 months of LPLV (fines!) Data Sharing (Data Sets) Requirement for NIH-funded studies Need to consider sharing with Participants, Sponsor, Community Prepare data sets for sharing Linked De-identified Anonymized Data Sharing with De-Identification Must be consistent with ICF Remove all HIPAA identifiers Replace original ID numbers with new ID numbers Remove geography data Recode dates to time intervals (reference point) Remove sensitive data not integral to study Recode or group other potential identifiers Low frequency medical conditions or procedures 24

26 Preparing Data Sets for Sharing CDISC, CDASH or CDEs SAS data sets Data Dictionary Annotated CRFs Data Sharing Partners Scientific Community Sponsor Repository NLM 25

27 Different Perspectives in Clinical Trials Text Scenario #1 Suzie, the Site Coordinator, is preparing to enroll the first subject in a multicenter clinical trial at her site. What preparations has the Coordinating Center made to prepare for this day? What considerations should Suzie and her PI be thinking about prior to enrolling the subject? What concerns does the Sponsor have about enrolling the first Subject? 26

28 Scenario #2 Tom, the Study Coordinator called a subject for a phone follow-up and learned that the subject had been hospitalized for pneumonia. How does the site know whether it was a Serious Adverse Event and how to report it? What does the Independent Medical Monitor need to review? What and when will the IRB need to review? What and when does the DSMB need to review? What are the Sponsors concerns and what will they need to review/report? Scenario #3 Sarah, the Study Coordinator, gets a letter from the Coordinating Center stating that they are sending a monitor to visit the clinical site next week! What preparations should the Site PI/coordinator be making? What is the Coordinating Center preparing for the visit? What are the Sponsors concerns? Scenario #4 A study on prevention of pediatric migraine has a planned interim analysis due to the DSMB in four weeks. What does the Site PI and coordinator have to worry about? What will the Coordinating Centers be doing to prepare the report? What will the DSMB be expecting to see? What are the Sponsor concerns? 27