36C24620Q0309-002.docx

Department of Veterans Affairs Office of Research & Development SAMVAMC Research and Development Service Nanoparticle Fabrication for TBI Research Performance Work Statement (PWS)

A. GENERAL INFORMATION

1. Title of Project: Nanoparticle fabrication for TBI research. Nanoparticles Mitigate Chronic Behavior and Neuropathology.

2. Background: Blast-related traumatic brain injury (bTBI) presents a significant concern for our Veteran population. Approximately 20% of Veterans returning from recent conflicts report with at least one mild TBI and 75% of all TBI reported by Veterans are associated with blast exposure. These injuries can have long-term effects involving physical, emotional, and cognitive symptoms. The overarching goal of this research is to test a novel therapy that can reduce the persistent behavioral and neuropathological effects observed after blast. The Lavik group has engineered a novel therapy that can halt the degeneration and may be able to eliminate or cure the neurological impacts of the trauma. Hemostatic nanoparticles (hNPs) developed in the Lavik Lab can be administered intravenously and have been shown to reduce bleeding and increase survival in multiple models of trauma. A significant advantage that hNPs have is that we can engineer versions to deliver therapeutic agents. Tempol, a free radical scavenger, has been shown to provide neuroprotection after acute central nervous system disease and traumatic injury. Its antioxidant function led to microvascular and axonal protection following single and repeated brain injury. Data from our preclinical blast models identified that oxidative stress and glial reactivity remains at least three months following blast TBI. Based on these results, this research proposes to develop drug-delivery hNPs to stop neurological degeneration following blast injury. Expanding the impact of the study, we will also test these particles to treat immediately after a second TBI.

Fig. 1: Schematic of hemostatic nanoparticles (hNPs)

3. Scope: This contract request is for the fabrication and analysis of particles needed to accomplish the goals of the VA Merit as it was funded. The Lavik Lab at UMBC will provide the nanoparticles that will be used as the treatment within the study. Fabrication and analysis of all particles will be conducted by the Lavik Lab, which include purity and accurate dosing for the regimens. Specifically, the Lavik Lab will fabricate the hNPs following our previous work (Shoffstall et al. 2012 and 2013). Briefly, PLGA-PLL-PEG-GRGDS is synthesized and formed into nanoparticles using a nanoprecipitation protocol. The particles are snap frozen and lyophilized with poloxamer 188 as a cryoprotectant. The polymer is characterized via GPC and NMR, and the particles are characterized via SEM and DLS as well as NMR to confirm degree of PEGylation. The peptide concentration is confirmed via amino acid analysis. Tempol is encapsulated by dissolving it in acrylonitrile along with the polymer at a 25 mg/ml concentration. The nanoprecipation procedure is carried out leading to encapsulation of Tempol. The loading is determined by incubating 10 mg of particles in DMSO overnight followed by UV-Vis to determine the amount encapsulated. The release curve is determined by incubating particles in an infinite sink system of PBS and extracting supernatant until Tempol cannot be measured for 72 hours following our previous work (Groynom et al. 2015). Bioactivity is confirmed using endothelial cells with Tempol and comparing their cellROX green staining to free Tempol to supernatant from encapsulated Tempol. Particles will be shipped overnight to the VandeVord lab at Virginia Tech to be used to complete the animal experiments. Year 4 funds are less as the fabrication will be less and tasks will focus on reporting of particle data.

4. Period of Performance: The period of performance (POP) shall be 48 months. The POP will begin with the date of Office of Management and Budget (OMB) approval.

5. Type of Contract: N/A

6. Place of Performance: The Contractor shall support this effort at approved Contractor facilities as directed by the Contracting Officer’s Representative (COR) and mutually agreed to by the Contractor.

B. GENERAL REQUIREMENTS

1. The contractor will present a plan for project organization and staffing that demonstrates a knowledge of effective organizational structure, management, and how best to utilize key and other personnel. The contractor will have the personnel, equipment, material, supplies, forms, and systems of computer programs to manage this study and process the data collected for this study, unless otherwise stated in a specific contract.

C. SPECIFIC MANDATORY TASKS AND ASSOCIATED DELIVERABLES

Task 1: Select Personnel The contractor will designate personnel considered essential to the work being performed under this contract. If any essential personnel are to be removed from the contract, whether planned or unplanned, the contractor will notify the VA COR and submit written justification, including the names and vitae of proposed substitutions, in sufficient detail. This will occur within 30 days before departure of the personnel or as soon as possible, if, for example, it is a result of the personnel ending employment with the contractor. The VA COR must concur with the diversion of personnel and approve the replacement. Also, the VA may modify the contract to add or delete key personnel at the request of the contractor. The contractor will designate a main contact for prompt administration during this contract.

Personnel working on this contract should have experience in areas including:

· Fabrication of hNPs following previous work at the Lavik Lab (Shoffstall et al. 2012 and 2013).

· Synthesizing nanoparticles using a nanoprecipitation protocol.

· Analysis of fabricated particles

· Confirmation analysis of peptide concentration via amino acid analysis.

· Loading analysis via UV-Vis to determine the amount encapsulated.

Deliverable 1 – Notification to VA re: details of essential personnel with justifications.

Deliverable 2 – Designation of an administrative contact.

Task 2: Regular Communication/Meetings and Recording Decisions The contractor and the VA investigator (Dr. Pamela VandeVord) will have an initial meeting within 2 weeks of the contract award to discuss and review the activities of the contract. Topics will include the overall project management plan and schedule. A draft agenda will be prepared by the contractor and approved by the VA investigator 3 days before the meeting.

The contractor must communicate every month with the VA investigator or designees within VA research team. The communications will take place over the telephone. The contractor will brief the COR and/or designees and survey research staff as to the status of the project, quality control findings, description of any problems anticipated or encountered and their resolution or non-resolution, and milestones obtained or missed. During active data collection, the contractor will report the number and percent of responses and compare the progress in the current survey cycle with that of the previous cycle.

The contractor will keep a log of decisions made during the course of the study and provide the VA COR with an updated log of any new decisions made following the weekly meeting within 7 business days following each meeting. After review of the decision log, the VA COR will provide any necessary corrections to the decision log, which then will be revised.

Deliverable 3 – Attend monthly meetings with the COR and VA study team and keep minutes of discussions.

Deliverable 4 – Keep log of study-related decision.

Task 3: Project Plan and Procedures The contractor will provide the following according to the agreed upon timeline below.

List of items/services to be covered by this agreement:

with GRGDS

with GRGDS peptide

TOTAL

For years 1-4 of the project, based on the proposal description, we will fabricate and characterize hemostatic nanoparticles and control nanoparticles delivering TEMPOL.

The dosing for these studies is 5 mg per rodent to account for the dose and loss. Based on this dosing and the number of rodents expected to receive particles, we anticipate making 300 mg of particles in year 1; 300 mg in year 2; 300 mg in year 3; and 150 mg in year 4. Based on the study design, we are assuming that we will use even numbers of the three groups in the model.

Year 1: 300 mg of particles and characterization across the 3 groups.

Year 2: 300 mg of particles and characterization across the 3 groups.

Year 3: 300 mg of particles and characterization across the 3 groups.

Year 4: 150 mg of particles and characterization across the 3 groups.

Noncontract Charges: The contractor shall not perform any service that will result in additional charges without prior approval from the Contracting Officer.

Task 4: Quality Assurance The contractor will develop a quality control plan that covers all aspects of the work to be performed under this contract. The quality control plan will include the following:

· The contractor will have a management system that identifies potential problems early, ensures high-quality data and adherence to schedules, controls project costs, and maintains close communication with the VA. Project operations will include frequent conversations concerning progress and challenges, meetings to discuss and resolve problems, and regular reporting between the contractor and the VA.

· The contractor has provided or will provide training to supervisors, laboratory staff, and other staff necessary for the project. This training must include study procedures and problem identification.

All contractor personnel will satisfy VA training requirements in privacy, information security, and any additional training related to research and information security as required.

· The contractor will conduct logic and range edit checks on all data and correct all errors that are resolvable using available information.

· The VA COR, together with other VA staff, will make announced and unannounced visits to monitor contractor operations on-site.

Deliverable 5 – Develop a quality control plan and update COR within 2 months of contract award.

Deliverable 6 – Develop a data management system to track progress of lab activity and reporting to VA Investigator.

Deliverable 7 – Set of data confirming purification and concentration of the hNPs within 3 months of contract award.

Task 5: Submit a Confidentiality Plan and Data Security Procedures Storage and Access to Data Data will be entered into separate, dated electronic databases on a weekly basis and the VA COR should be notified when complete. The VA shall have electronic access to all databases. A cumulative file of all records should be created and maintained by the contractor.

Data Security The contractor will ensure the highest degree of security to protect data from intentional or unintentional release, loss, or destruction. Prior to receipt of any data files from the VA, the contractor will submit a confidentiality plan and data security procedures for approval by the VA COR and revise it per the VA COR instructions. Contractors, contractor personnel, subcontractors, and subcontractor personnel shall be subject to the same Federal laws, regulations, standards, and VA Directives and Handbooks as VA and VA personnel regarding information and information system security.

Data will be transferred, retained, utilized, and destroyed in accordance with VA and VHA policy including the following: VA Handbook 5011/5, Chapter 4 (Alternative Workplace Arrangements); VA Directive and Handbook 6500, Information Security Program; VA Directive and Handbook 6502, Privacy Program; and VHA Directive 1605, VHA Handbook 1605.1 and 1605.2.

Deliverable 8 – Submit a Data Security Procedure Plan

D. SCHEDULE OF DELIVERABLES

See Attachment A

E. INSPECTION AND ACCEPTANCE CRITERIA

Final inspection and acceptance of all work performed, reports and deliverables will occur at the place of delivery designated by the COR. Final approval and acceptance of documentation required herein shall be by letter of approval and acceptance by COR. The Contractor shall not construe any letter of acknowledgment of receipt of material as a waiver of review, or as an acknowledgment that the material is in conformance with this PWS.

F. CHANGES TO STATEMENT OF WORK

Any changes to this PWS shall be authorized and approved only through written correspondence from the CO.

A copy of each change will be kept in a project folder along with all other products of the project. Costs incurred by the contractor through the actions of parties other than the CO shall be borne by the contractor.

G. GOVERNMENT RESPONSIBILITIES

The government shall assure that the contractor has access to VA toll-free telephone numbers for Veterans as appropriate.

H. KEY PERSONNEL

The Contractor shall be responsible for managing and overseeing the activities of all Contractor personnel, as well as subcontractor efforts used in performance of this effort. The Contractor's management responsibilities shall include all activities necessary to ensure the accomplishment of timely and effective support, performed in accordance with the requirements contained in the statement of work.

The Contracting Officer may notify the Contractor and request immediate removal of any personnel assigned to the task order by the Contractor that are deemed to have a conflict of interest with the government or if the performance is deemed to be unsatisfactory. The reason for removal will be documented and replacement personnel shall be identified within three business days of the notification. Employment and staffing difficulties shall not be justification for failure to meet established schedules.

The PI, Dr. VandeVord, will provide oversight of the entire program, including the development and implementation of all policies and procedures. In these roles, she will be responsible for the implementation of the proposed experiments. She will run the animal components of the proposal and assure compliance with all institutional animal research policies. Dr. VandeVord will hold primary responsibility for characterization of injury and neurobehavioral characteristics. Dr. VandeVord will coordinate particle optimization. Additionally, Dr. VandeVord will assume all fiscal management and the grant will be managed through the Department of Research at the Salem VAMC. Dr. VandeVord will share responsibility for the overall analyses and integration of the data. Publication authorship will be based on the relative scientific contributions of the PI, Co-Investigators, and other personnel. Data will be shared with the outside scientific community via publications and presentations at scientific and professional meetings. Research progression, conflicts about the scientific direction of the grant, administrative and/or fiscal matters will be discussed by both groups during monthly video conference meeting.

1. Key Personnel: TBD

2. Substitution of Key Personnel: All Contractor requests for approval of substitutions hereunder shall be submitted in writing to the COR and the Contracting Officer at least thirty (30) calendar days in advance of the effective date, whenever possible, and shall provide a detailed explanation of the circumstances necessitating the proposed substitution, a complete resume for the proposed substitute, and any other information requested by the Contracting Officer necessary to approve or disapprove the proposed substitution. New personnel shall not commence work until all necessary security requirements, as defined in Section J, have been fulfilled and resumes provided and accepted. The COR and the Contracting Officer will evaluate such requests and promptly notify the Contractor of approval or disapproval in writing.

I. PERSONNEL QUALIFICATIONS:

a. Successful contractor shall have personnel with a proven track record of providing medical monitoring programs for high risk occupational groups, as well as designing and providing web and other communications activities.

b. Personnel must be experienced in enrollment of workers, performance of work history interviews and review of exam reports and Results Letters.

c. The Contractor shall document that the qualifications of the professional, technical and administrative staff proposed are adequate for full performance of tasks. Curriculum Vitae (CVs) or detailed bios are provided for each proposed staff member.

d. The Contractor shall identify the key roles and specific responsibilities for each key role of the professional, technical and administrative staff proposed.

e. The Contractor shall demonstrate the appropriate mix and balance of education, academic excellence, training and experience of proposed team members.

f. The Contractor shall ensure that proposed program managers and senior level professionals are qualified, and available for consultation with VA from 8 am EST to 6 pm PST.

J. SECURITY

Information System Security The contractor shall ensure adequate LAN/Internet, data, information, and system security in accordance with VA standard operating procedures and standard contract language, conditions laws, and regulations. The contractor’s firewall and web server shall meet or exceed the government minimum requirements for security.

All government data shall be protected behind an approved firewall. Any security violations or attempted violations shall be reported to the VA project manager and the VHA Headquarters Information Security Officer as soon as possible. The contractor shall follow all applicable VA policies and procedures governing information security, especially those that pertain to certification accreditation.

Security Training All contractor employees and subcontractors under this contract or order are required to complete the VA's on-line Security Awareness Training Course and the Privacy Awareness Training Course annually. Contractors must provide signed certifications of completion to the CO during each year of the contract. This requirement is in addition to any other training that may be required of the contractor and subcontractor(s).

M. SECTION 508

The contractor shall comply with Section 508 of the Rehabilitation Act (29 U.S.C. § 794d), as amended by the Workforce Investment Act of 1998 (P.L. 105-220), August 7, 1998.

In December 2000, the Architectural and Transportation Barriers Compliance Board (Access Board), pursuant to Section 508(2) (A) of the Rehabilitation Act Amendments of 1998, established Information Technology accessibility standards for the Federal Government. Section 508(a)(1) requires that when Federal departments or agencies develop, procure, maintain, or use Electronic and Information Technology (EIT), they shall ensure that the EIT allows Federal employees with disabilities to have access to and use of information and data that is comparable to the access to and use of information and data by other Federal employees. The Section 508 requirement also applies to members of the public seeking information or services from a Federal department or agency.

Section 508 text is available at:

http://www.opm.gov/HTML/508-textOfLaw.htm http://www.section508.gov/index.cfm?FuseAction=Content&ID=14

N. CONFIDENTIALITY AND NONDISCLOSURE

It is agreed that:

1. The preliminary and final deliverables and all associated working papers, application source code, and other materials deemed relevant by the VA which have been generated by the contractor in the performance of this task order are the exclusive property of the U.S. Government and shall be submitted to the CO at the conclusion of the task order.

2. The CO will be the sole authorized official to release verbally or in writing, any data, the draft deliverables, the final deliverables, or any other written or printed materials pertaining to this task order. No information shall be released by the contractor. Any request for information relating to this task order presented to the contractor shall be submitted in writing to the CO for response.

3. Press releases, marketing material or any other printed or electronic documentation related to this project, shall not be publicized without the written approval of the CO.

4. The Contractor will sign a National Business Associate Agreement with the VA, in accordance with the mandated guidelines.

O. RIGHTS IN DATA

Performance of this effort may require the contractor to access and use data and information proprietary to a Government agency or Government contractor which is of such a nature that its dissemination or use, other than in performance of this effort, would be adverse to the interests of the Government and/or others.

Contractor and/or contractor personnel shall not divulge or release data or information developed or obtained in performance of this effort, until made public by the Government, except to authorize Government personnel or upon written approval of the Contracting Officer (CO). The contractor shall not use, disclose, or reproduce proprietary data that bears a restrictive legend, other than as required in the performance of this effort. Nothing herein shall preclude the use of any data independently acquired by the contractor without such limitations or prohibit an agreement at no cost to the Government between the contractor and the data owner which provides for greater rights to the contractor.

The Department of Veterans Affairs shall have unlimited rights to and ownership of all deliverables provided under this effort, including reports, recommendations, briefings, work plans and all other deliverables. This includes the deliverables provided under the basic award as well as and any optional task deliverables that are exercised by the Contracting Officer. The definition of “unlimited rights” is contained in Federal Acquisition Regulation (FAR) 27.401, Definitions.

P. TASK ORDER TERMINATION

VA has the right to terminate (in whole or in part) this task order at any time in accordance with the termination clauses of the governing GSA Schedule Contract. The Contractor will be paid only for the services rendered up to the point of receiving the termination notice, and then only to the extent that those services meet the requirements of this SOW.

Q. CONTRACT ADMINISTRATION:

Notwithstanding the Contractor's responsibility for total management during the performance of this contract, the administration of the contract will require maximum coordination between the Government and the Contractor. The following individuals will be the Government's points of contact during the performance of this contract:

2. Contracting Officer’s Technical Representative (COR): To be designated at time of contract award.

The COR shall be designated on the authority of the Contracting Officer at the time of contract award to monitor all technical aspects of the contract. In no event is the COR empowered to change any of the terms and conditions of the contract. Changes in any section of this contract shall be made only by the Contracting Officer pursuant to a properly executed modification. The types of actions within the purview of the COR’s authority are to ensure that the Contractor performs the technical requirements of the contract, and to notify both the Contractor and the Contracting Officer of any deficiencies observed. A memorandum of designation shall be issued to the COR and a copy shall be sent to the Contractor at the time of contract award setting forth in full the responsibilities and limitations of the COR

Attachment A

Note that the Deliverable Table is directly related to the tasks and deliverables in Section C above.

Schedule of Deliverables

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