Tools for Conduct of Early Phase Clinical Trials

Transcription

1 Tools for Conduct of Early Phase Clinical Trials 8th Meeting with International Partners for Influenza Vaccine Technology Transfer to Developing Country Vaccine Manufacturers Rahnuma Wahid, PhD Technical and Project Coordinator, Vaccine Development March 17, 2015

2 Develop a realistic timeline Include: Manufacturing and product readiness Length of time of review and approval of protocol dossier (various submissions) Contract negotiation and finalization Time to develop and rollout trial data capture system and site startup activities Trial recruitment/enrollment and implementation Time to complete clinical study report following database lock Awareness of regional influenza season

3 Example of Gantt Chart for clinical trial see appendix 1 See appendix 1 for detailed Gaant chart for clinical trials Page 3

4 Examples of Roles and Responsibilities Chart for Phase 1 Influenza trial See appendix 2 for Roles and Responsibilities chart for clinical trials Page 4

5 Discussion/Questions What are some important items to remember when planning for a clinical trial? What are the benefits of planning ahead for a clinical trial? Who should be involved in planning for a trial? What is the advantage of having a clear roles and responsibilities (R&R) chart? Where should the R&R chart be documented? Page 5

6 Activity and timeline chart for seasonal flu phase yellow highlights indicate expected timelines Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec red is milestone Complete Phase 1 process and manufacturing activities Develop production process for Ph 1 materials Confirm production process for Ph1 materials Develop release assays for Ph 1 materials (using development mono bulk) Develop limited validation plan (SRID, protein, triton for bulk & final product) Provide bulk validation samples to QC (e.g. from development lots) Formulate Final product from development lots Limited validatation of FP release assays for Ph1 ( from development lots) Produce consistency monovalent bulk for AH1N1 (3 lots) Produce consistency monovalent bulk for AH3N2 (3 lots) Produce consistency monovalent bulk for B/Mass (3 lots) Release consistency monovalent lots Evaluate stability of Ph 1 bulks (9 lots) at 2-8C Formulate final product(fp) & fill finish (clinical lots) Release tox/clin lot for non-clinical testing (if not using dev lots) Release Ph 1 materials for Ph 1 clinical trial (national lab release, if required) Evaluate stability of Ph 1 FP (label claim & accelerated temps) Milestone: Tox and Ph1 materials manufactured and released Conduct non-clinical studies Conduct immunogenicity POC studies (mice, dose response study) Conduct GLP toxicology study (per regulatory guidelines) Milestone: Non-clinical tudies completed (reports finalized)

7 Activity and timeline chart for seasonal flu phase Prepare for Ph1 clinical trial Prepare clinical documents Define clinical development plan and study design Develop Ph1 protocol and related documentation Protocol and ICFs IB (complete after tox study is done and with at least 3 mon stability data) pcrf/ecrf Diary card/memory card (not a source doc) MOP (manual of procedure) SSP (study specific procedure) Laboratory manual Pharmacy manual Milestone: Earliest submission of dossier to institutional IRB Milestone: Earliest submission of dossier to MOH ERC Milestone: Earliest submission of dossier to WHO ERC Milestone: Ph 1 clinical documents finalized Select Ph1 clinical trial partners& bid process Site assessment by questonnaire Site assessment by site visit Select 1 clinical trial site(s) Select Ph1 clinical trial CROs (trial monitoring and data management) Select Ph1 clinical trial laboratory Select Ph1 immunology laboratory Identify PSRT members Milestone: Ph 1 clinical trial partners selected Negotiate and sign contracts with Ph1 study partners Clinical trial agreement prep and execution (with RACI) Negotiate and sign contracts with clinical site(s) (sponsor and site(s)) Negotiate and sign contracts with clinical laboratory Negotiate and sign contracts with immunology laboratory Negotiate and sign contract with monitoring CRO or independent monitors Negotiate and sign contract with data management CRO

8 Activity and timeline chart for seasonal flu phase Milestone: Ph1 clinical trials contracts with partners signed Prepare Ph1 study partners (after contracts executed) Prepare Ph1 clinical site(s) (training &MoH training, SOPs) Prepare labs, develop (or check if already qualified) assays for Ph 1 testing (safety and immunological) DM CRO CRF prep DM CRO database setup, validation, training and rollout Statistical analysis plan (SAP) Safety and site monitoring plans Milestones: Ph 1 infrastructure & operations prepared Regulatory and ethics Consult MoH/regulatory agency in pre-ph1 meetings Submit petition for seasonal trial to MoH, if required Submit CT dossier to institutional IRB and obtain approval Submit and obtain WHO ERC approval Submit and obtain MoH/regulatory agency ERC approval Milestones: Phase 1 MoH, site IRB & WHO ERC approvals obtained Conduct Ph 1 clinical trial Site initiation visit First subject, first visit Implementation With continuous review of safety data by PSRT & expert Last subject, last visit Data Analysis & CSR Draft tables, listings, figures Query resolution, data cleaning, casebooks complete & signed Database lock Delivery of final TLFs CSR prep (english)

9 Activity and timeline chart for seasonal flu phase CSR final (and translate as needed) Submission to local IRB and approval Submission to MoH and approval Phase 1 trial complete

10 ROLES AND RESPONSIBILITIES FOR CLINICAL TRIALS Phase I - Safety and Immunogenicity CLINICAL S Vaccine Developer Supporting Institution CRO - Global CRO - Local TBD Vaccine Program R = party which is Responsible for carrying out the activity A = party which Approves outcome C = party which is Consulted and provides input to party R I = party which is Informed of the outcome of the activity A STUDY DOCUMENTS Vaccine Supporting 1 Clinical Trial Agreement (3-party Agreement: PATH/Vaccine Dev/Site) A R A I I 2 Clinical Trial Insurance R A C I C 3 CRO Agreement (PATH, Vaccine Dev, CRO) R A C A C 4 CRO Agreement (PATH, Vaccine Dev, LOCAL CRO) A R C C A 5 Draft protocol synopsis R A C I I 6 Design clinical study R A C I I 7 Author and finalize protocol R A C I I 8 Author future protocol amendments R A C I I 9 Final scientific protocol review R A C I I 10 Provide Package Insert / IB to site R C C I I 11 Develop clinical monitoring plan and monitoring tools A A C R R 12 Develop safety monitoring plan and monitoring tools A A C R R 13 Develop internal project communication plan R A C I I 14 Develop protocol-specific procedures R A I C C 15 Draft and finalize ICF(s) R A C I I 16 Revise ICF based on protocol amendments R A C I I 17 Translate all relevant documents into local languages (i.e., ICF, CRFs, etc.) A A R I R 18 Prepare final study report R A I I I

11 B STUDY PREPARATION Vaccine Supporting 1 Develop overall site budget A R R I C 2 Study staff identified, recruited, and hired at site A A R C C 3 Prepare randomization plan A A I R I 4 Plan and execute Lead Investigator Meeting - R A C I I 5 Plan and execute investigators meeting R A C I I 6 Provide GCP and ethics training to site A A C C R 7 Train site staff on protocol-specific procedures A A I R R 8 Coordinate site IRB submissions and obtain approvals, including annual renewals A A A I R 9 Coordinate overall IRB submissions and WIRB submissions and obtain approvals, including annual renewal R A I I I 10 Regulatory submissions and annual renewals R A I I I 11 Track Local IRB renewals I I A I R 12 Obtain regulatory approvals and documents required for study initiation A A A I R 13 Track status of regulatory and study initiation documents R A A C A 14 Monitor and track site readiness status A R C C C 15 Register trial with international clinical trial registry R A C C C 16 Labs assessed for GLP and proficiency R A C C C 17 Monitoring organization identified A R C C C 18 Protocol issued to investigative staff R A C I I 19 Site SOPs developed A A C C R 20 SOPs relating to cold chain maintenance developed A A C I R 21 ICFs and CRFs printed and transported to site A A C R C 22 Ensure adequate supply of ICFs and CRFs throughout study period C C A R A 23 Pretrial cold-chain assessment A A C C R 24 Pre-study progress reporting A A C R R 25 Prepare and maintain study site regulatory binders C C R C R C STUDY IMPLEMENTATION Vaccine Supporting 1 Site and lab financial management C R R I I 2 Overall site study implementation according to project timelines A A R R R 3 Recruit, screen, enroll, vaccinate and follow up study participants according to protocol C C R C R 4 Attend to and report safety events C C R R R 5 Set up and plan monthly conference calls A A C R R

12 6 Attend monthly conference calls R R R R R 7 Maintain and archive study files according to ICH/GCP C C R C C 8 Generate project reports which will include: enrollment, laboratory, SAE, demographic data updates A A C R R D PRODUCT/CLINICAL SUPPLIES Vaccine Supporting 1 Procure study vaccine R C C I R 2 Procurement, transport, and storage of EPI Vaccines C C C C R 3 QC of study vaccine prior to purchase and shipment (check expiration dates and country import requirements) R I I I I 4 Provide shipment information to site R I I I R 5 Storage / Inventory management/accountability of study and EPI vaccines at site A A R I A 6 Reconciliation/accountability and maintenance of clinical supplies at site A A R I A 7 Cold chain assurance and maintenance by site A A R I A E LABORATORIES Vaccine Developer Supporting Institution 1 Clinical laboratory testing serum C C R I A 2 Clinical laboratory testing swabs C C R I A 3 Shipment of serum samples to lab by contract shipment company C C R I C 4 Reconcile discrepancies in serum samples received at the laboratory C C R I R 5 Reconcile discrepancies in swab samples received at the laboratory C C R I R 6 Provide serum clinical safety testing results for merging with database R C I A I 7 Provide RSV assay (immuno) testing results for merging with database R C I A I 8 Provide swab testing results for merging with database R C I A I F GCP MONITORING CRO INC CRO - Local Vaccine Supporting 1 Conduct pre-study visit C C C A R 2 Facilitate investigators meeting (Target date = TBD) C C C C R 3 Facilitate Site Investigators Leaders meeting (Target date = TBD) R R C C C 4 Conduct site initiation visit A A C R R 5 Conduct site monitoring visits C C C A R

13 6 Ensure completeness of regulatory binders at site on a regular basis C C C C R 7 Monitor refrigerator and freezer storage temperature logs, track and report temperature deviations I I C C R 8 Maintain record of communications / conversations related to study conduct (telephone, faxes, etc) I I C C R 9 Review CRFs and assure resolution of findings I I C R R 10 Monitor specimen tracking and lab records I I C C R 11 Monitor documentation on ICFs, SAEs (100%) I I C C R 12 Prepare monitoring reports and follow-up letters I I C C R 13 Review monitoring reports R R C C C 14 Clinical monitoring oversight A A C R R 15 Follow-up on monitoring report findings A A C C R 16 Conduct study site closeout visit C C C C R 17 Monitor cold chain 18 Monitor laboratory compliance 19 Ensure completeness of regulatory binders at site at end of study A A C C R G SAE REPORTING AND MONITORING Vaccine Developer Supporting Institution CRO INC CRO - Local 1 Provide Independent Medical Monitor/ SAE medical review A A C R C 2 Establish 24-hour coverage for SAEs A A C R C 3 Ensure that the SAE reporting guidelines are followed A A C R C 4 Write initial and follow-up SAE reports C C C R C 5 Maintain SAE log C C C R C 6 Enter SAEs into study Database C C R C C 7 Track subjects who discontinue due to SAEs until resolution C C R C C 8 Prepare safety letters to be distributed to IRBs R A C C C 9 Perform SAE reconciliation with DM database C C C R C 10 Perform overall review of safety data R R C C C 11 Track all SAEs and provide list to Vaccine Dev DSMB at predetermined intervals A A C R C H REGULATORY AFFAIRS Vaccine Supporting 1 Compile documents for regulatory submission R C C C A 2 Submit periodic study reports to regulatory authorities, as required A A A C R 3 Submit periodic SAE reports to the regulatory authorities, as required A A C A R

14 4 Submit final study report to regulatory authorities A A C C R 5 Provide responses to regulatory questions A A C C R I Vaccine Supporting 1 Develop, finalize, and update data management plan A C C R C 2 Develop, finalize, and update other guidelines like data coding guidelines, quality plan, edit check specifications, data review and monitoring plan A C I R I 3 Design Case Report Forms and other data collection tools A C C R C 4 Develop, finalize and update data entry and handling guidelines for data collection /monitoring /clean-up A C C R C 5 Produce, validate, review all tables, listings and graphs/figures for final study report authoring post database freeze A C C R C 6 Develop, test, deploy and release the database A C I R I 7 Perform data entry C C R C A 8 Develop, finalize and update Data Validation Plan C C C R C 9 Resolve data queries C C C R C 10 Conduct data cleaning C C C R C 11 Data certified as accurate C C C R C 12 Merge lab results with clinical database C C C R C 13 Track timely database entry of CRFs C C R R C Provide access to data or periodic reports as needed to ensure consistency and data 14 quality. C C C R C 15 Create transport files (in Excel format or other pre-defined format) C C C R C 18 Lock completed database and transport to Vaccine Dev/PATH/statistician for analysis C C I R I 19 Perform ongoing audit of database and report results to the sponsor A C C R C 20 Store and archive study records/crfs A C C R C J DATA MANAGEMENT STATISTICS Vaccine Developer Supporting Institution 1 Develop and finalize statistical design and analysis plan R A I R I 2 Statistical Programming R I I R I 3 Conduct analysis according to statistical analysis plan R C I R I 4 Generate draft statistical report for review R C I R I 5 Final statistical report reviewed with comments R A I R I 6 Generate final statistical report R A I C I 7 Manuscript of results drafted R C C C I 8 Manuscript of results submitted for publication R C C C I CRO INC CRO - Local K QUALITY CONTROL AND ASSURANCE

15 Vaccine Supporting 1 Provide ongoing Quality Control for study site implementation C C I C R 2 Perform Quality Assurance / Site Visits if needed R R I C C 3 Reconcile challenges identified during QA and provide responses A A C C R 4 Provide ongoing Quality Control/Quality Assurance for serum laboratory A A C C R 5 Provide ongoing Quality Control/Quality Assurance for swabs laboratory A A C C R 6 Provide ongoing Quality Control/Quality Assurance for immunology laboratory R A C C C