3_Updated Transfer of Obligation Table for the Draft Protocol Synopsis 02-09-2023.pdf

UPDATED TRANSFER OF OBLIGATION TABLE (February 14, 2023) for Area of Interest 9.7 Attachment: Protocol Synopsis and Example Transfer of Obligation Table

Phase 2 clinical trial platform investigating multiple therapeutic options for the treatment of hospitalized patients with acute respiratory distress syndrome (ARDS) protocol synopsis

Transfer of Obligation Table (Updated February 14, 2023)

R: Responsible

A: Accountable

C: Consulted

I: Informed

Coordinate all Offeror‐provided activities within the parameters established by BARDA as the trial sponsor, including: BARDA

Clinical

CRO

Drug Sponsor

1.0 Project Management:

Create project management plan that addresses the following components (program coordination, implementation, quality assurance/quality control oversight for entire program, risk management and mitigation) Provide admin support to coordinate meetings (pull from ABESt) C A/R I

Develop and maintain a study responsibility assignment matrix for Offeror and subcontractor team. The responsibility matrix will be shared with BARDA regularly as requested. C A/R I

Provide weekly/monthly update reports C A/R I

Track and maintain study timelines in MS Project and provide weekly updates to BARDA C A/R I

Set up and maintain a web‐based informational study portal C A/R I

Track and maintain study budget C A/R I

Schedule, provide agenda, and lead project team meetings.

Document team decisions and action items in meeting minutes and a decision log C A/R I

Project Team Training C A/R I

Attend and follow up meetings with drug sponsor C A/R I including: BARDA

Clinical

CRO

Drug

Prepare Project Plans (Project Management Plan, Communication Plan, Medical Monitoring Plan, Risk Management, Investigational Product and Clinical Supplies management plan, Data Management Plan, IVRS/IWRS Plan, Specimen/Lab Management Plan, Clinical Site Monitoring Plan, etc.) C A/R I

Establish and maintain a Risk Register that is reviewed at each BARDA/CRO team meeting C A/R I

Coordination of insurance policies C A/R I

Plan, conduct, and attend investigators’ meeting(s) C A/R I

Provide written minutes of the investigators’ meeting(s) C AR I

2.0 Clinical Monitoring and Site Management Activities

2.1 Clinical Monitoring/Site Mgmt. (Start Up)

Study Documents

Print and distribute Protocol, ICFs, IB C A/R I

Develop Study Manuals (e.g., Manual of Procedures, Pharmacy Manual, Regulatory Binder, etc.) C A/R I

Print and distribute Study Manuals I A/R I

Make all relevant internal SOPs available for BARDA review I A/R I

Author, as needed, any internal Standard Operating Procedures (SOPs) associated with processes necessary to comply with FDA and Sponsor established requirements, as directed by the Sponsor. Required SOPs may include procedures for all relevant Sponsor Responsibilities listed in 21CFR312 regulations and may incorporate both Sponsor and CRO activities. C A/R I

Develop and distribute study‐specific source document templates in parallel with Case Report Forms (CRF) as appropriate I A/R I

Site/Investigator Identification and Qualification

Develop feasibility questionnaire and site selection plan C A/R I

Develop list of potential sites C A/R I

Conduct site feasibility I A/R I

Conduct pre‐study visits I A/R I

Select study sites and investigators C A/R I

Pre‐Study Activities

Confidentiality Agreements C A/R I

Prepare site contracts C A/R I

Negotiate and execute all clinical trial agreements and site contracts (budgets) C A/R I

Prepare indemnification/liability statement C A/R I

Review and evaluate for completeness all elements of informed consent for all sites I A/R I

Collect, review, and file Essential Documents I A/R I including: BARDA

Clinical

CRO

Drug

Site Initiation Visits

Conduct site initiation visits including protocol specific training I A/R I

Provide/Review source documents – CRFs, study test article records, etc. I A/R I

Provide training of site personnel including training updates as needed I A/R I

Additional Training

Train site personnel in GCP and HSP I A/R I

Train necessary site personnel in GCLP and IATA I A/R I

Patient Recruitment

Develop and execute recruitment and retention plans, monitor site recruitment retention as well as subject visit compliance C A/R I

Develop advertisements and ensure IRB approval prior to use C A/R I

2.2 Clinical Monitoring/Site Mgmt. (Conduct)

Site Monitoring Visits

Conduct interim on‐site monitoring visits I A/R I

Review and verification of available source documentation to the CRFs I A/R I

Verify investigators’ compliance with protocol and regulatory requirements I A/R I

Obtain corrections to CRFs/query resolution I A/R I

Maintain site training of personnel I A/R I

Provide written site monitoring reports within 10 business days of a site visit I A/R I

Site Management

Maintain log of trial questions/answers (FAQ) I A/R I

Manage study site supplies (non‐IMP) I A/R I

Participate in scheduled conference calls with sites C A/R I

Perform off site clinical review of CRFs I A/R I

Administer investigator/site payments I A/R I

Maintain regular contact with sites I A/R I

Perform records management I A/R I

Translate official/study documents I A/R I

2.3 Clinical Monitoring/Site Mgmt. (Close Out)

Close Out Activities

Conduct close out visits I A/R I

Arrange/Ensure investigators documents archiving I A/R I

Communication of study results to investigators C A/R I

Provide written site closeout reports I A/R I including: BARDA

Clinical

CRO

Drug Sponsor

2.4 Clinical Monitoring/Site Mgmt. (Lab Monitoring/Pharmacy/Unblinded Monitoring/Other)

Investigational Product Management

Perform unblinded monitoring visits I A/R I

Review Investigational Product and comparator agent placebo accountability records I A/R I

Review Investigational Product and comparator agent placebo temperature storage records I A/R I

Return unused supplies/IMP/ comparator agents placebos to drug depot for destruction and/or for final disposition C A/R C

Perform post study test article accountability I A/R I

Specimen Management

Manage on site samples I R/A I

Review storage temperature of samples stored onsite I R/A I

Organize specimens’ removals/shipments I R/A I

Forecast/Schedule specimens’ removals/shipments C R/A C

3.0 Regulatory

3.1 Regulatory Support and Consulting

Regulatory Document (Essential Documents) Packets collection and regulatory review I R/A I

Coordination of IP (Investigational Medicinal Product) Import/Export Licenses with BARDA product Program I R/A I

Archive final FDA submission study documents I R/A I

Arrange and conduct Regulatory agency meetings C R/A I

Create eTMF Index C R/A I

Set up eTMF I R/A I

Maintain eTMF I R/A I

Final eTMF QC/Archiving/Document Return C R/A I

3.2 EC/IRB Support

EC/IRB Initial Submission C R/A I

EC/IRB Annual Report Submission C R/A I

EC/IRB Amendment Submission C R/A I

Ensure selected central and local IRBs have Federal Wide Assurance (FWA) throughout study I R/A I

3.3 Regulatory Operations

Develop Common Technical Document (CTD) submission build list C R/A I

Update build list in real time for needed submission documents, delivery dates and Offeror’s dates as submission build progresses C R/A I

Quality Control the final IND word documents and convert them to Submission Ready PDF files I R/A I including: BARDA

Clinical

CRO

Quality control, publish, and submit via the FDA Electronic Submission Gateway, FDA submissions compliant with electronic CTD (eCTD) specifications and all applicable regulatory requirements I R/A I

Validate eCTD submissions and provide to BARDA the complete validation report before final approval to submit to FDA I R/A

N/A

Provide BARDA all correspondence with the FDA, including submissions, acknowledgments I

R/A

Archive final FDA submission package I R/A N/A

Provide submission metrics (number of pages, hyperlinks, bookmarks) and other relevant information as needed I R/A

Provide a concatenated submission document to be used for printing and archiving I R/A

Register and provide information for clinical studies to ClinicalTrials.gov Protocol Registration and Results System

(PRS) I A/R I

Manage record in ClinicalTrials.gov PRS I A/R I

Review essential documents for approval and site activation I A/R I

Periodically review study eTMF for completion and provide findings I A/R I

4.0 Pharmacovigilance

Prepare Safety Monitoring Plan C A/R C

Establish and maintain 24‐hour hotline for SAE coverage I A/R I

Setup and maintain Safety Database C A/R I

Setup and maintain unblinding responsibility I A/R I

Receive, Review, Report and Track Safety Events C A/R I

Entry, coding, and QC of SAEs in safety database I A/R I

Perform SAE reconciliation of safety database. Provide SAE reconciliation SOP if safety database separates from clinical database. I A/R I

Preparation of SUSARs/Expedited safety reports C A/R I

Distribute SUSARs/Expedited Reports/Investigator Alert Notifications to sites I A/R I

Submit SUSARs/Expedited Reports to National Regulatory Authorities I A/R I

Submit SUSARs/Expedited Reports to EC/IRB I A/R I

Submit SUSARs to FDA I A/R I

Attendance at an investigator meeting I A/R I

Provide safety status and maintenance reports C A/R C

Transfer final SAE database C A/R C

Safety Monitoring Committee (SMC), Scientific Steering Committee and Adjudication Committee including: BARDA

Clinical

CRO

Select and approve SMC, Scientific Steering Committee, and Adjudication Committee members C A/R I

Develop and approve SMC, Scientific Steering Committee, and Adjudication Committee Charter C A/R I

Prepare data for SMC, Scientific Steering Committee, and Adjudication Committee meetings (blinded and unblinded) C A/R I

Manage SMC, Scientific Steering Committee, and Adjudication Committee meeting process including blinded and unblinded minutes I A/R I

5.0 Quality Assurance

Conduct TMF (Trial Master File) Audits I A/R I

Functional Organization Chart (Staffing detail and responsibilities) I A/R I

List all Contract Manufacturing Organizations (CMO), including CROs and Laboratories I A/R I

Report Out of Specification or other failures in Lab or CMO within 5 days of occurrence I A/R I

Audit/inspection preparation I A/R I

Conduct investigator site and subcontractor audit(s) C A/R I

Database audit(s) I A/R I

Study report audit I A/R I

6.0 Data Management

Electronic Case Report Form (eCRF)

Design and draft eCRFs including annotated CRF C A/R I

Finalize (Approve) eCRFs C A/R I

Translate eCRFs if needed I A/R I

Develop eCRF Completion guidelines C A/R I

Electronic Data Capture (EDC) Training C A/R I

Develop and finalize additional source data forms (e.g., diary) C A/R I

Data Management Set Up

Build and design clinical study database based on approved eCRFs C A/R I

User Acceptance Testing (UAT) of database C A/R I

Develop Data Edit Checks C A/R I

Program Data Edit Checks C A/R I

Test Data Edit Checks I A/R I

Provide/restrict database access/data export to authorized personnel I A/R I

Develop/maintain screening log/database if not included in the clinical study database I A/R I

Develop/maintain protocol deviation log/database if not included in the clinical study database C AR I

Data Management (General) including: BARDA

Clinical

CRO

Drug Sponsor

Develop Data Management Plan and Data Validation Plan C A/R I

Provide draft data monitoring reports as requested C A/R I

Data review and query generation and resolution C A/R I

Adverse event coding (MedDRA) C A/R I

Medical History coding (MedDRA) C A/R I

Concomitant Medication coding (WHOdrug) C A/R I

Develop Patient Data Listings C A/R I

Program Patient Data Listings C A/R I

Review Patient Data Listings C A/R I

Provide SAE Form ‐ CRF SAE reconciliation C A/R I

Electronic lab data loading I A/R I

Management of local lab normal ranges I A/R I

Reconciliation of lab, safety, immunology data, etc. I A/R I

Perform database QC check I A/R I

Perform database audit I A/R I

Database freeze/lock I A/R I

Archive database I A/R I

Provide data reports and study specific metrics C A/R I

Provide automated notifications of safety events (designated per protocol) C A/R I

Retain final electronic data I A/R I

Database Transfers

Program according to BARDA format (SAS datasets) C A/R I

Test/QC data transfer C A/R I

Deliver interim data transfer(s) consisting of a SDTM file containing at a minimum, the dm, ae, lb, dv domains C A/R I

Deliver final data transfer I A/R I

7.0 Biostatistics

Randomization Services

Develop randomization scheme/schedule C A/R I

Review randomization scheme/schedule C A/R I

Develop interactive voice/web response system (IV/WRS) C A/R I

User Acceptance Testing (UAT) of IV/WRS database C A/R I

Statistical Analysis

Author Statistical Section of Protocol C A/R I

Review Statistical Section of Protocol C A/R I

Develop Statistical Analysis Plan C A/R C

Review Statistical Analysis Plan C A/R C

Approve Statistical Analysis Plan C A/R C

Develop SDTM and ADaM Dataset C A/R I including: BARDA

Clinical

CRO

Drug Sponsor

Program SDTM and ADaM Dataset I A/R I

Validate SDTM and ADaM Dataset I A/R I

Perform statistical data quality checks I A/R I

Support IDMC/DSMB meetings I A/R I

Produce and validate tables, listings and figures (TLFs) for ad hoc analyses/ DSMB/CSR I A/R I

Review tables, listings and figures for adhoc analyses/DSMB/CSR C A/R I

Author the Stat Section of Clinical Study Report and Review the CSR C A/R I

Provide Additional Statistical Analysis Required by FDA C A/R I

Provide Responses to FDA Questions that are Statistical Nature in Regulatory Submission C A/R I

Data Transfers and Submission

Prepare data transfer agreement C A/R I

Review data transfer agreement C A/R I

Approve data transfer agreement C A/R I

Provide regulatory submission data components (define.xml, SAS XPT datasets, aCRFs, RG etc.) C A/R I

Provide complete source SAS programs for reproducing final analysis datasets and efficacy analyses C A/R I

Provide BARDA a copy of regulatory submission data components C A/R I

Provide BARDA source SAS programs for reproducing all data analysis outcomes, including interim, final, and additional regulatory submission related analyses C A/R I

8.0 Medical Monitoring

Medical Management (24‐hour MD consultation for investigator sites and project team members, protocol questions) C A/R I

Review of Lab results C A/R C

Review of ECG results C A/R C

Review of AE, SAE, PIMMC, MAAE data for safety trends C A/R C

9.0 Medical Writing and Report Publishing Activities

Design study C A/R C

Write protocol C A/R C

Approve protocol C A/R C

Write protocol amendments C A/R C

Approve protocol amendments C A/R C

Translate Protocol or protocol summary (if required) I A/R I

Prepare template Informed Consent Form (ICF); site questionnaires; diaries and any subject‐facing documents as needed C A/R C including: BARDA

Clinical

CRO

Translate template Informed Consent Form (ICF) , diaries and any subject‐facing documents I A/R I

Prepare Investigational Brochure (IB) N/A N/A N/A

Translate Investigational Brochure (IB) N/A N/A N/A

Author original IND submission documents for Module 1 (general investigational plan, IB, study rationale, labels, Form FDA 3674) C A/R I

Original IND submission documents for Module 2 (CMC, Nonclinical, Clinical Summary Documents) C A/R A/R

Original IND submission documents for Module 3 (CMC documents as needed) C A/R A/R

Original IND submission documents for Module 4 (Nonclinical Reports) C A/R A/R

Original IND submission documents for Module 5 (Protocol, 1572, CV, IRB, SAP, Sample CRF, Clinical Study Report) C A/R I

IND amendments including changes to CTD Modules 1 through 5 C A/R I

Author other IND documents as needed C A/R I

Safety reports C A/R I

IND annual reports C A/R I

Write patient narratives C A/R I

Draft Clinical Study Report (s) C A/R I

Review Clinical Study Report(s) C A/R I

Finalize Clinical Study Report(s) C A/R I

Prepare manuscripts C A/R I

Retain final electronic study reports C A/R I

10.0 Third Party Vendor Management

Management of Central Lab vendor I A/R I

Management of Drug Depot vendor I A/R I

Management of ECG vendor I A/R I

Management of Translations vendor I A/R I

Management of IVRS vendor I A/R I

Management of CRF Printing vendor I A/R I

Management of Meeting Planner I A/R I

Management of Data Management vendor I A/R I

Management of Patient Recruitment vendor I A/R I

Other (Please Specify)

11.0 Other Outsourced Activities (Please Specify)

Clinical Supply Management

Supply study test article and comparator agentplacebo I I A/R

Package study test article and comparator agentplacebo I I A/R

Label study test article and comparator agentplacebo I I A/R including: BARDA

Clinical

CRO

Drug Sponsor

Store study test article and comparator agentplacebo I A/R I

Distribute study test article and comparator agentplacebo I A/R I

Develop Investigational Product Accountability Plan and study test article and comparator agent placebo accountability logs I A/R I

Manage study test article and comparator agent placebo accountability records I A/R I

Return unused supplies/study comparator placebos to drug depot for destruction or final disposition I A/R C

Destroy study test article/comparatorplacebo I A/R C

Pharmacokinetic (PK) Data Analysis

Provide PK analysis text to statistical analysis plan N/A N/A N/A

Evaluate plasma concentration data for possible reassays N/A N/A N/A

Provide interim analysis(es) N/A N/A N/A

Provide final analysis N/A N/A N/A

Provide PK/PD Modeling (check only if applicable) N/A N/A N/A

Consulting Activities

Provide medical/clinical consulting C A/R I

Provide biopharmaceutical/pharmacokinetics consulting N/A N/A N/A

Provide regulatory consulting N/A N/A N/A

Provide general consulting N/A N/A N/A