AOI 9.7 Draft Protocol Synopsis.pdf

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

Rationale for Proposed Clinical Trial There are no FDA-approved treatments for acute respiratory distress syndrome (ARDS).

Identifying new treatments for patients with ARDS remains challenging since ARDS is a highly heterogeneous syndrome. Many drugs have been tested in previous clinical trials with no success, although post-hoc analyses often provide positive signals in subsets of patients with ARDS. Therefore, there is an urgent need to understand the clinical and biological features to better classify patients into sub-phenotypes that might be more responsive to a given therapy.

This phase 2 platform trial will evaluate novel host-directed therapies in hospitalized adults diagnosed with ARDS regardless of the causal etiology. As a hypothesis-generating study, this phase 2 trial is intended to gather as much data as possible on the ARDS patient population to better inform future clinical studies. In addition, an exploratory biomarker study will be included to identify patients who may benefit from specific host-targeted mechanisms of action and perhaps identify triggers for treatment. Specifically, this phase 2 trial is designed to collect relevant clinical and biological markers that can define subsets of patients with ARDS who may benefit from specific host-targeted therapeutics. As a phase 2 trial, the results are not intended to be pivotal, but the trends seen within the data may help identify patients most likely to benefit from the candidate intervention and inform the design of a registrational phase 3 clinical trial.

Given the exploratory nature of this study, this phase 2 platform trial will have a master protocol encompassing all cohorts with criteria on data collection, endpoints, and conduct of the overall program. Each product will have its own cohort of patients through study completion. The Sponsor may choose the appropriate ARDS severity to enroll for their candidate therapeutic. If the Sponsor entering this phase 2 trial has identified a target ARDS subpopulation for their investigational product (IP), the study cohort may consider enrolling only those patients who meet the criteria to test the hypothesis before entering phase 3. Each product will have its own protocol appendix, Statistical Analysis Plan (SAP), and subsequent study report as agreed between BARDA and the Sponsor. The Sponsor may suggest a specific biomarker analysis plan for their study cohort.

Cohort data/outcomes will be confidential to Biomedical Advanced Research and Development Authority (BARDA) and the Sponsor as agreed in a data-sharing agreement until results are published. It is not anticipated that placebo arms would be shared/pooled between cohorts since there may be challenges regarding product blinding and variable start times per cohort.

However, with Sponsor concurrence, sharing placebo arms may be a consideration for products with similar routes of administration and dosing in which blinding could be maintained.

Due to the significant heterogeneity in patients with ARDS, no interim efficacy and futility assessments are planned for this phase 2 trial. There is no intent that any individual cohort’s completion and closeout would depend on other ongoing cohorts. BARDA will have a core SAP for data analyses at the completion of all cohorts to allow the pooling of data across cohorts to inform BARDA and investigators regarding subgroups, biomarkers, and endpoints in ARDS.

However, there is no plan to compare treatment arms/therapeutic products across individual cohorts directly. In addition, Sponsors must agree to publish study results and biomarker analyses to participate in the trial.

Study Design This is a master protocol synopsis for a platform clinical trial to evaluate three phase 2-ready host-directed therapeutic candidates in hospitalized patients diagnosed with ARDS. The safety and efficacy of each product will be studied in its own patient cohort with selected ARDS severity at baseline regardless of the causal etiology in a multicenter, randomized, double-blind, placebo-controlled fashion.

Each cohort can commence as the Sponsor and sites have institutional review board (IRB)/independent ethics committee (IEC) approvals and are ready to begin enrollment; the master protocol allows for the inclusion of new cohorts as new treatments are introduced. Each Sponsor/product will have its own protocol appendix, SAP, subsequent study report, and its own cohort of subjects with a level of ARDS severity upon which BARDA and Sponsor are agreed. Sponsor will provide the investigational product (IP) and matching placebo for their cohort. The Offeror will manage the labeling, kitting, depot, and shipping of study materials and supplies, including IP and placebo.

Patients will be randomized 2 to 1 to either the IP given with standard of care (SOC) or to a placebo/SOC control arm per cohort. The most likely inciting cause of ARDS for each patient will be captured. Patients will be stratified by level of ARDS severity and the identified or suspected inciting cause (e.g., viral, bacterial, aspiration, etc.) of ARDS at randomization. Enrolled patient population will have no more than 30% of COVID-19 patients and no more than 60% of patients enrolled with viral causes of ARDS. Other stratification factors may be considered. However, patients with ARDS associated with physical injury/trauma will be excluded.

Subjects will be assessed daily while hospitalized in the primary institution. Subjects discharged from the hospital will be asked to attend study visits on Days 15, 22, 30, 60, and 90. Home health care services may be considered for patient follow-up visits post-discharge from the primary facility. All subjects will undergo a series of efficacy, safety laboratory assessments, and biomarker evaluations per the preliminary schedule of events below. In all cohorts, an additional assessment includes an 8-point ordinal scale (i.e., from death to not hospitalized, no limitations on activities) while hospitalized and in follow-up visits.

There is no plan to conduct interim analyses for futility/efficacy for this phase 2 trial. However, an independent data safety monitoring board (DSMB) will assess patient safety routinely, and study arms will be terminated at any time if the DSMB finds evidence of risk to patient safety.

In addition, BARDA will develop the SAP in partnership with Sponsors for the IP vs. placebo in individual cohorts as well as for pooled data across treatment or placebo groups to assess biomarkers of disease and therapeutic response.

Study Objectives and Endpoints/Outcomes All assessments are by individual cohort, evaluating the novel treatment vs. placebo with SOC.

Additionally, the core SAP will outline analyses performed for pooled data.

The primary objective is to evaluate the efficacy of the IP relative to the control arm, and outcomes will be assessed based on the level of baseline ARDS severity at randomization:

• For cohorts treating patients with mild ARDS at baseline, the primary efficacy outcome is the proportion of subjects alive and free of invasive mechanical ventilation/ECMO at Day 30.

• For cohorts treating patients with moderate to severe ARDS at baseline, the primary efficacy outcome is all-cause mortality at Day 30.

Given the exploratory nature of this study, as many assessments as appropriate and possible will be conducted in all subjects and assessed as per the master protocol/core SAP. Primary outcome assessments will be at Day 30; however, further assessments will be collected at Days 60 and 90.

OBJECTIVES ENDPOINTS & OUTCOME MEASURES

• Clinical efficacy of the investigational product (IP) relative to the control arm.

• Proportion of subjects alive and free of invasive mechanical ventilation/ECMO at Day 30

• All-cause mortality at Day 30

• Oxygenation and Ventilation

• Daily oxygenation in the two groups until Day 30

• Days of supplemental oxygen (if applicable)

• Oxygenation-free days to Day 30

• Incidence and duration of new oxygen use during the study

• Non-invasive ventilation/high-flow oxygen:

o Non-invasive ventilation/high-flow oxygen-free days to Day 30 o Incidence and duration of new non-invasive ventilation or high-flow oxygen use during the study o Days of non-invasive ventilation (if applicable) o Days of high-flow oxygen (if applicable)

• Invasive Mechanical Ventilation/ECMO o Days of invasive mechanical ventilation at Day 30 o Incidence of new mechanical ventilation or ECMO use during the study o Duration of mechanical ventilation or ECMO use during the study o Ventilator/ECMO free days to Day 30

• Time to recover gas exchange to a PaO2/FiO2 ≥ 300 for at least 24 hours during the first 30 days after enrollment

• Proportion of subjects needing (i.e., ECMO, intra-aortic balloon pump, ventricular assist devices [VADs]) through Day 30

• Time to extubation

• Mortality • 14-day all-cause mortality

• 60-day all-cause mortality

• 90-day all-cause mortality

• Ordinal outcomes:

o Death and cause of death (if applicable) o Hospitalized, on invasive mechanical ventilation or

ECMO;

o Hospitalized, on non-invasive ventilation or high-flow oxygen devices;

o Hospitalized, requiring supplemental oxygen;

o Hospitalized, not requiring supplemental oxygen -requiring ongoing medical care o Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;

o Not hospitalized, limitation on activities and/or requiring home oxygen;

o Not hospitalized, no limitations on activities

• Time to an improvement of one category and two categories from Day 1 (baseline) using an ordinal scale

• Subject clinical status using an ordinal scale on Days 3, 5, 8, 11, 15, 22, 30, 60, and 90

• Mean change in the ordinal scale from Day 1 to Days 3, 5, 8, 11, 15, 22, 30, 60, and 90

• Clinical outcome assessed using an ordinal scale daily while hospitalized and on Days 15, 22, 30, 60, and 90

• Hospitalization • Days of hospitalization

• Days of intensive care unit (ICU) stay

• Safety

• Adverse Events (AEs)/Serious Adverse Events (SAEs); SAEs after Day 30

• Laboratory assessments to include hematology (White blood cell count with differential, hemoglobin, platelets), chemistry panel (e.g., creatinine, glucose), and liver function tests (e.g., total bilirubin, ALT, and AST) on Day 1;

Days 3, 5, 8, and 11 (while hospitalized); and Days 15 and 30 (if attends in-person visit, visited by a home health aid, or still hospitalized)

• Evaluate biomarkers of progression and/or response in

ARDS

• Evaluate biomarkers in whole blood, serum, plasma, and/or tracheal aspirate (TA) fluid from baseline to end of treatment for prognosis, therapeutic impact, and triggers for treatment in all subjects by Days 1, 3, 5, 8, 11, 15, 30, and if hospitalized, at Days 60 and 90

• Pulmonary functional imaging to assess baseline (Day 1) and changes from baseline to Day15 and Day 30, with assessment as possible at Day 60 and Day 90

Inclusion Criteria

1) Male or non-pregnant female adult ≥18 years of age at the time of enrollment.

2) Subject (or legally authorized representative) provides written or electronic informed consent prior to initiation of any study procedures.

3) Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.

4) Hospitalized with signs and symptoms of ARDS according to the Berlin definition of ARDS

(ATS 2012).

a) Respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid overload (an objective assessment of cardiac failure or fluid overload is needed if no risk factors for ARDS are present).

b) Radiological abnormalities on chest X-ray or computerized tomography scan, i.e., bilateral opacities that are not fully explained by effusions, nodules, masses, or lobar/lung collapse.

c) Significant hypoxemia to be classified as mild, moderate, or severe ARDS.

i) Mild ARDS (all of the following):

• Clinical assessment (evidence of rales/crackles on an exam) AND SpO2 ≤ 94% on room air, AND

• Hypoxemia: PaO2/FiO2 >200 mmHg (>26.6 kPa) to ≤300 mmHg (≤39.9 kPa) with positive end-expiratory pressure (PEEP) ≥5 cmH2O, AND

• Requiring supplemental oxygen, AND

• Does not require mechanical ventilation

ii) Moderate ARDS:

• Hypoxemia: PaO2/FiO2 >100 mmHg (>13.3 kPa) to ≤200 mmHg (≤26.6 kPa) with PEEP ≥5 cmH2O

iii) Severe ARDS:

• Hypoxemia: PaO2/FiO2 ≤100 mmHg (≤13.3 kPa) with PEEP ≥5 cmH2O.

d) The radiological and hypoxemia criteria must be met within the same 24-hour period.

The time of onset of ARDS is when the last of the two specified ARDS criteria is met.

5) Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception, not including hormonal contraception, from the time of screening through Day 30.

6) Subject agrees to not participate in another investigational interventional trial through Day 30.

Exclusion Criteria

1) Subjects with ARDS or at risk of developing ARDS due to physical injury or trauma.

2) Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test.

3) Anticipated transfer to another hospital which is not a study site within 72 hours.

4) Subject is not expected to survive for 72 hours.

5) Subject has been on mechanical ventilation or ECMO for more than 48 hours.

6) Subject has an underlying clinical condition where, in the opinion of the Investigator, it would be extremely unlikely that the subject would come off ventilation, e.g., motor neurone disease, Duchenne muscular dystrophy, or rapidly progressive interstitial pulmonary fibrosis.

7) Subject has severe chronic obstructive pulmonary disease requiring long-term home oxygen therapy or mechanical ventilation (non-invasive ventilation or via tracheotomy) except for continuous positive airway pressure (CPAP) or bi-level positive airway pressure used solely for sleep-disordered breathing.

8) Subject has congestive heart failure, defined as New York Heart Association Class IV.

9) Subject has an acute left ventricular failure.

10) Allergy to any study medication.

11) Subject has a liver failure (Child–Pugh grade C).

12) Estimated glomerular filtration rate (eGFR) < 50 or requiring dialysis prior to hospitalization.

13) Subject receiving immunosuppressive therapy for solid organ or hematopoietic cancer or transplant anti-rejection medication.

14) Subject is undergoing active cancer chemotherapy.

15) Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

Study Phase

Phase 2

Study Population

Hospitalized adults (≥18 years old) with ARDS; estimate ~ 200 subjects per cohort.

A more diverse patient population with ARDS will be expected to enroll in the trial. Currently, it is presumed that infectious causes of ARDS will predominate. However, no more than 30% of randomized subjects will have COVID-19 as an inciting cause, and no more than 60% of subjects overall will have ARDS due to respiratory viral infections, including SARS-CoV-2. The remaining ARDS cases could be due to other causes, including bacterial pneumonia, chemical aspiration, unknown causes, etc.

Study Sites

There will be up to 50 sites within the US.

Study Intervention

The trial is designed to evaluate multiple interventions in separate cohorts. IPs will be assessed for incorporation into the trial based on in vitro, preclinical in vivo, phase 1 clinical safety data, and available clinical data supporting an ARDS indication. Sponsors will provide IP and matching placebo ready for labeling/kitting and distribution by the CRO in addition to supporting any regulatory submissions required for the study.

Subjects will be enrolled in cohorts as described above and randomized to treatment. The trial will have two arms per cohort, and subjects will be randomized to receive either an active product or placebo as follows:

• IP will be administered as {TBD}.

• A matching placebo will be given on the same schedule.

Below are two treatment regimen examples that may study in cohorts for pricing considerations:

• Cohort Example #1: 200 patients randomized 2:1 to Treatment 1 vs. placebo, treated q8h by one-hour IV infusion for 14 days

• Cohort Example #2: 200 patients randomized 2:1 to Treatment 2 vs. placebo, treated q8h orally (including protocols for intubated patients) for 30 days

The master protocol for the trial platform will be reviewed and approved by the IRBs/IECs and applicable regulatory agencies before implementation. In addition, as new interventions/cohorts are added, the master protocol will be amended to add the new cohort’s specific protocol appendix to be reviewed by the IRBs/IECs and applicable regulatory agencies before implementation. The master protocol, however, does lay out the general principles of how the multi-intervention trial would be implemented with ARDS enrollment criteria, efficacy and safety assessments, endpoints/outcomes, and biomarker evaluations.

Study Duration

The study will last for up to 3 years. Note that individual cohorts may start and stop independently of the other ongoing cohorts. Offeror may propose an alternative timeline with rationale.

Participant Duration

An individual subject will complete the study in about 90 days, from screening on Day -1 or 1 to follow-up on Day 90 ± 3 days. Home health care services may be considered for patient follow-up visits as needed post discharge from the primary facility.

Safety

Blinded pools of Grade 3 and 4 adverse events (AEs)/severe AEs (SAEs) data will be reviewed per a regular schedule. Only SAE data will be collected after Day 30. The DSMB may be asked to review unblinded safety data in ad hoc meetings.

The DSMB will review safety data after every 50 subjects per cohort and will be available for ad hoc reviews for safety concerns as described above. The DSMB may recommend temporary or permanent cessation of enrollment based on their safety reviews.

Specimen Collection & Processing

1. Blood samples (whole blood/serum/plasma) will be collected in ALL patients:

• Screening: 10 ml of whole blood for safety and pregnancy tests

• Days 1, 3, 5, 8, 11, 15, and 30: 10 ml of whole blood at each time point for safety test

2. Blood samples will be collected in ALL patients: whole blood/serum/plasma and PBMCs will be aliquoted and stored at -80°C in a central laboratory for biomarker assays or future research use (e.g., multi-omics exploratory analysis, etc.)

Cohort 1, company 1 Treatment 1 Mild ARDS

Cohort 2, company 2 Treatment 2 Mild ARDS

Cohort 3, company 3 Treatment 3 Moderate ARDS

Cohorts enrolled per sponsor/product who chooses ARDS severity of illness for study;

these are just examples

Pa�ents randomized per cohort 2-1 to novel treatment/SOC vs blinded placebo/SOC.

Treatment 1 + SOC

Treatment 3 + SOC

Placebo 1 + SOC

Treatment 2 + SOC

Placebo 2 + SOC

Placebo 3 + SOC

Pla�orm of clinical sites to enroll ARDS pa�ents; management team manages CROS for site management, stats, data management. Protocol defines ARDS severity, stra�fica�on, enrollment, data collected and endpoints that are common across cohorts

This structure allows

• BARDA control of data with contractual agreement on data sharing

• Ability to collect data in ARDS treated and placebo pa�ents

• Limit the noise that is inherent in ARDS studies esp with heterogenous pa�ents groups

This structure allows

• each cohort/product to start and end enrollment independent of other cohorts

• Depending on �ming, cohorts could poten�ally share placebo data

• Protocol can detail pooled data analyses for pooled biomarkers across placebo groups as well as treatment groups within context of data sharing agreement

Day 30 primary endpoint

Day 30 primary endpoint

Day 30 primary endpoint

• Days 1, 3, 5, 8, 11, 15, 22, 30, 60, and 90 (when hospitalized or home health care services are accessible): 5 ml of whole blood for serum; 5 ml of whole blood for plasma; 10 ml of whole blood for PBMC isolation and cryopreservation; 2.5 ml of whole blood in PAXgene Blood RNA Tube

• Day 1: Additional 20 ml of whole blood for microbiological diagnostic tests

3. Tracheal Aspirate (TA) specimens will be collected under sterile conditions via special catheters from the endotracheal tube in mechanically ventilated patients or by direct tracheal suction in tracheotomized patients. TA supernatant and cell pellet will be processed and stored at -80°C in a central laboratory for biomarker assays or future research use (e.g., multi-omics exploratory analysis, etc.)

• Days 1, 3, 5, 8, 11, 15, 22, 30, 60, and 90 (when hospitalized): Recovered TA specimen for collecting supernatant and the cell pellet

• Day 1: Save 2 ml of TA specimen for microbiological diagnostic tests

Schedule of Assessments (SOA)

Screen Baseline7 Study Intervention Period

Follow-up Visits

Day +/- Window ± 1 1 (± 1) Daily until hospital discharge (± 1)

(± 1)

(± 1)

(± 3)

(± 3)

ELIGIBILITY

Informed consent X

Inclusion/Exclusion X

Demographics X

Medical history X

Concomitant medications X

Physical exam including height/weight X

Confirm diagnosis of ARDS X

Assess inciting event leading to

ARDS X

Chest radiography (x-ray or CT) X

STUDY INTERVENTION

Randomization X

Administration of IP or control

As per regimen by product

STUDY PROCEDURES

Vital signs including SpO2

X Daily until discharge X X X X10 X10

Blood Cultures X2 X Prn as indicated while hospitalized

Microbiological diagnostic testing as appropriate to potential ARDS cause1

X

Critical illness scoring (APACHE, SAPs, SOFA, or MPM) X

Concomitant medications X Day 3, 5, 8, 11 if hospitalized8 X X X X X

Clinical data collection (Including assessment of Clinical Ordinal Scale)2

X Daily until discharge X X11 X X11 X11

Targeted physical exam X Day 3, 5, 8, 11 if hospitalized8 X X X X X

Adverse event evaluation

X Daily until discharge X X X X12 X12

Pulmonary functional imaging3 X (± 2 days) Day 8 (± 2 days) X X X X

SAFETY LABORATORY

Safety hematology, chemistry, and liver function tests (Central laboratory)

X5,6 X 7,8,9 Day 3, 5, 8, 11 (all ±

1 day) if hospitalized8,9

X13 X13

Pregnancy test for females of childbearing potential X5,6

RESEARCH LABORATORY

Samples for biomarker (TBD) testing4 X (up to

± 1 day) Day 3, 5, 8, 11 (all ± 1 day) if hospitalized X X X14 X14 X14

Notes:

1 Including but not limited to respiratory specimens, oropharyngeal or nasal swabs, or blood or tissue cultures, depending on the potential event leading to ARDS 2 Clinical data to be collected, including 8-point ordinal scale score, documentation of respiratory support level, oxygen requirement (PaO2, FiO2, PaO2/FiO2 ratio), mechanical ventilator requirement status, etc.

3 Methods TBD 4 Final biomarker collection TBD; analyses could include but not be limited to IL-8, IL-6, TNF-a, Protein C, CRP, procalcitonin, and others as per sponsor discussion.

5 Screening laboratory tests include ALT, AST, creatinine (estimated glomerular filtration rate, eGFR), and a pregnancy test.

6 Laboratory tests performed in the 24 hours prior to randomization will be accepted for determination of eligibility.

7 Baseline assessments should be performed prior to randomization. Laboratory tests performed as part of routine clinical care in the 24 hours prior to the first dose will be accepted for the baseline safety laboratory tests. The baseline may be the same as the screening laboratory tests.

8 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, and AST.

9 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory reporting.

10 Patients are expected to come back for in-person visits or use home health care services.

11 Home health care services may be considered at Days 22, 60, and 90 if the subject is discharged to assess clinical status (ordinal scale), hospital readmission, and mortality only.

12 Serious Adverse Events (SAEs) will be only reported after Day 30.

13 Safety laboratory tests on Days 15 and 30 if still hospitalized or returns to the site for a visit.

14 Sample collection for biomarkers on Days 30, 60, and 90 if still hospitalized or home health care services are accessible.

Transfer of Obligation Table 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

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 including: BARDA

Clinical

CRO

Drug

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, file Essential Documents I A/R I 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 including: BARDA

Clinical

CRO

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

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 accountability records I A/R I

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

Return unused supplies/IMP/ comparator agents 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 including: BARDA

Clinical

CRO

Drug Sponsor

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

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

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 including: BARDA

Clinical

CRO

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 Set-up 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

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 including: BARDA

Clinical

CRO

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) 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 including: BARDA

Clinical

CRO

Drug Sponsor

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 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 including: BARDA

Clinical

CRO

Drug Sponsor

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

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 including: BARDA

Clinical

CRO

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 agent I I A/R Package study test article and comparator agent I I A/R Label study test article and comparator agent I I A/R Store study test article and comparator agent I A/R I Distribute study test article and comparator agent I A/R I

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

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

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

Destroy study test article/comparator 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 including: BARDA

Clinical

CRO

Drug Sponsor

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

Transfer of Obligation Table