Tools for Conduct of Early Phase Clinical Trials

Rahnuma Wahid, PhD Technical and Project Coordinator, Vaccine Development

March 17, 2015

8th Meeting with International Partners for Influenza Vaccine Technology Transfer to Developing Country Vaccine Manufacturers

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

Develop a realistic timeline

Example of Gantt Chart for clinical trial see appendix 1

Page 3

See appendix 1 for detailed Gaant chart for clinical trials

Examples of Roles and Responsibilities Chart for Phase 1 Influenza trial

Page 4

• See appendix 2 for Roles and Responsibilities chart for clinical trials

Discussion/Questions

Page 5

• 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?

Activity and timeline chart for seasonal flu

phase 1

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 materialsDevelop 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 lotsLimited 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)

2014 2015 2016

Activity and timeline chart for seasonal flu

phase 1 2014 2015 2016

Prepare for Ph1 clinical trial

Prepare clinical documents

Define clinical development plan and study design

Develop Ph1 protocol and related documentation

Protocol and ICFsIB (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 laboratoryNegotiate and sign contract with monitoring CRO or

independent monitors

Negotiate and sign contract with data management CRO

Activity and timeline chart for seasonal flu

phase 1 2014 2015 2016

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)

Activity and timeline chart for seasonal flu

phase 1 2014 2015 2016

CSR final (and translate as needed)

Submission to local IRB and approval

Submission to MoH and approval

Phase 1 trial complete

Phase I - Safety and Immunogenicity

CLINICAL SITES

Vaccine Developer

Supporting Institution

CRO - Global

CRO - Local

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

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Clinical Trial Agreement (3-party Agreement: PATH/Vaccine Dev/Site) A R A I I2 Clinical Trial Insurance R A C I C3 CRO Agreement (PATH, Vaccine Dev, CRO) R A C A C4 CRO Agreement (PATH, Vaccine Dev, LOCAL CRO) A R C C A5 Draft protocol synopsis R A C I I6 Design clinical study R A C I I7 Author and finalize protocol R A C I I8 Author future protocol amendments R A C I I9 Final scientific protocol review R A C I I

10 Provide Package Insert / IB to site R C C I I11 Develop clinical monitoring plan and monitoring tools A A C R R12 Develop safety monitoring plan and monitoring tools A A C R R13 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 I16 Revise ICF based on protocol amendments R A C I I17 Translate all relevant documents into local languages (i.e., ICF, CRFs, etc.) A A R I R18 Prepare final study report R A I I I

TBD

Vaccine Program

ROLES AND RESPONSIBILITIES FOR CLINICAL TRIALS

STUDY DOCUMENTS

B

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Develop overall site budget A R R I C2 Study staff identified, recruited, and hired at site A A R C C3 Prepare randomization plan A A I R I4 Plan and execute SITE Lead Investigator Meeting - R A C I I5 Plan and execute investigators meeting R A C I I6 Provide GCP and ethics training to site A A C C R7 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

9Coordinate overall IRB submissions and WIRB submissions and obtain approvals,

including annual renewalR A I I I

10 Regulatory submissions and annual renewals R A I I I

11 Track Local IRB renewals I I A I R12 Obtain regulatory approvals and documents required for study initiation A A A I R13 Track status of regulatory and study initiation documents R A A C A14 Monitor and track site readiness status A R C C C15 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 C18 Protocol issued to investigative staff R A C I I19 Site SOPs developed A A C C R20 SOPs relating to cold chain maintenance developed A A C I R21 ICFs and CRFs printed and transported to site A A C R C22 Ensure adequate supply of ICFs and CRFs throughout study period C C A R A23 Pretrial cold-chain assessment A A C C R24 Pre-study progress reporting A A C R R25 Prepare and maintain study site regulatory binders C C R C R

C

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Site and lab financial management C R R I I2 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

STUDY PREPARATION

STUDY IMPLEMENTATION

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

8Generate project reports which will include: enrollment, laboratory, SAE, demographic

data updatesA A C R R

D

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Procure study vaccine R C C I R

2Procurement, transport, and storage of EPI Vaccines

C C C C R

3QC 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 R5 Storage / Inventory management/accountability of study and EPI vaccines at site A A R I A6 Reconciliation/accountability and maintenance of clinical supplies at site A A R I A7 Cold chain assurance and maintenance by site A A R I A

E

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Clinical laboratory testing—serum C C R I A2 Clinical laboratory testing—swabs C C R I A3 Shipment of serum samples to lab by contract shipment company C C R I C4 Reconcile discrepancies in serum samples received at the laboratory C C R I R5 Reconcile discrepancies in swab samples received at the laboratory C C R I R6 Provide serum clinical safety testing results for merging with database R C I A I7 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

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Conduct pre-study visit C C C A R2 Facilitate investigators meeting (Target date = TBD) C C C C R3 Facilitate Site Investigators Leaders meeting (Target date = TBD) R R C C C4 Conduct site initiation visit A A C R R5 Conduct site monitoring visits C C C A R

PRODUCT/CLINICAL SUPPLIES

LABORATORIES

GCP MONITORING

6 Ensure completeness of regulatory binders at site on a regular basis C C C C R

7Monitor refrigerator and freezer storage temperature logs, track and report temperature

deviationsI I C C R

8Maintain 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 R10 Monitor specimen tracking and lab records I I C C R11 Monitor documentation on ICFs, SAEs (100%) I I C C R12 Prepare monitoring reports and follow-up letters I I C C R13 Review monitoring reports R R C C C14 Clinical monitoring oversight A A C R R15 Follow-up on monitoring report findings A A C C R16 Conduct study site closeout visit C C C C R17 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

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

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 C5 Maintain SAE log C C C R C6 Enter SAEs into study Database C C R C C7 Track subjects who discontinue due to SAEs until resolution C C R C C8 Prepare safety letters to be distributed to IRBs R A C C C9 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

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Compile documents for regulatory submission R C C C A2 Submit periodic study reports to regulatory authorities, as required A A A C R3 Submit periodic SAE reports to the regulatory authorities, as required A A C A R

SAE REPORTING AND MONITORING

REGULATORY AFFAIRS

4 Submit final study report to regulatory authorities A A C C R5 Provide responses to regulatory questions A A C C R

I

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Develop, finalize, and update data management plan A C C R C

2Develop, 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

4Develop, finalize and update data entry and handling guidelines for data collection

/monitoring /clean-up A C C R C

5Produce, 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 I7 Perform data entry C C R C A8 Develop, finalize and update Data Validation Plan C C C R C9 Resolve data queries C C C R C

10 Conduct data cleaning C C C R C11 Data certified as accurate C C C R C12 Merge lab results with clinical database C C C R C13 Track timely database entry of CRFs C C R R C

14Provide access to data or periodic reports as needed to ensure consistency and data

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 C20 Store and archive study records/CRFs A C C R C

J

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

1 Develop and finalize statistical design and analysis plan R A I R I2 Statistical Programming R I I R I3 Conduct analysis according to statistical analysis plan R C I R I4 Generate draft statistical report for review R C I R I5 Final statistical report reviewed with comments R A I R I6 Generate final statistical report R A I C I7 Manuscript of results drafted R C C C I8 Manuscript of results submitted for publication R C C C I

K QUALITY CONTROL AND ASSURANCE

DATA MANAGEMENT

STATISTICS

Vaccine

Developer

Supporting

InstitutionSITE

CRO

INC

CRO -

LocalComments

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 C3 Reconcile challenges identified during QA and provide responses A A C C R4 Provide ongoing Quality Control/Quality Assurance for serum laboratory A A C C R5 Provide ongoing Quality Control/Quality Assurance for swabs laboratory A A C C R6 Provide ongoing Quality Control/Quality Assurance for immunology laboratory R A C C C