ARSBAA-06Mar08FinalCleanBV.pdf

UUU...SSS... DDDeeepppaaarrrtttmmmeeennnttt ooofff HHHeeeaaalllttthhh aaannnddd HHHuuummmaaannn SSSeeerrrvvviiiccceeesss Office of the Assistant Secretary for Preparedness and Response (ASPR)

Biomedical Advanced Research and Development Authority (BARDA)

BAA-BARDA-08-08

Therapies for Hematopoietic Syndrome, Bone Marrow Stromal Cell Loss, and Vascular Injury Resulting From Acute Exposure to Ionizing Radiation

OMB control number 0990-0115

1. OFFERORS ARE RESPONSIBLE FOR ROUTINELY CHECKING THE FOLLOWING WEBSITE FOR ANY

BAA AMENDMENTS. NO ADDITIONAL NOTIFICATION OF ANY AMENDMENTS WILL BE PROVIDED

BY THIS OFFICE. http://www.fedbizopps.gov/

2. BAA/CONTRACT FORM – PURCHASE AUTHORITY: FAR 1.602-1

NOTE: The issuance of this BAA does not commit the USG to an award.

3. Issue Date:

March 6, 2008

4. Due Date: April 17, 2008 Time: 4:00 p.m. , EST

5. Small Bus. Set-Aside: [ ]Yes [X] No 8(a) Set-Aside: [ ]Yes [X] No

NAICS #: 541712

6. Reserved

7. Number of Awards:

[ ] Only 1 Award [X] Multiple Awards

8. Technical Proposal Page Limits:

Number of Copies: See Attachment 1 (Packaging and Delivery of Proposals) Page Limits: 200 pages, including all appendices, CV’s and attachments.

10. [X] BARDA reserves the right to make awards without discussions.

9. Issued By:

David Beck, Contracting Officer Biomedical Advanced Research and Development Authority (BARDA) 330 Independence Ave., SW, Room G640 Washington, D.C. 20201

11. Options:

[X] No [ ] Yes

12. Period of Performance:

Up to three (3) years beginning on or about September 16, 2008.

13. Primary Point of Contact:

Name : Carl A. Newman Phone: 202-205-1156 Fax: 202-205-0873 E-Mail: carl.newman@hhs.gov

14. Secondary Point of Contact:

Name: David Beck Phone: 202-260-0453 E-Mail: david.beck@hhs.gov

15. Protest Officer:

Address: See Block 9

16. COLLECT CALLS WILL NOT BE ACCEPTED. FACSIMILE SUBMISSIONS ARE NOT ACCEPTABLE.

17. Offers will be valid for 120 days unless a different period is specified by the Offeror.

DELIVERY ADDRESS INFORMATION

18. Hand Delivery or Overnight Service:

N/A

19. U.S. Postal Service or an Express Delivery Service Biomedical Advanced Research and Development Authority Assistant Secretary for Preparedness and Response U.S. Department of Health & Human Services 330 Independence Ave. S.W., Room G640 Washington, D. C. 20201

20. The Official Point of Receipt for the purpose of determining timely delivery is the address provided in Block 19, above.

The original paper copy with original signatures is the official copy for recording timely receipt. If the original paper copy of your proposal is not received by the Contracting Officer or Designee at the place and time specified, then it will be considered late and handled in accordance with HHSAR 352.215-70 entitled "Late Proposals and Revisions" located in this

BAA. FACSIMILE SUBMISSION OF PROPOSALS IS NOT ACCEPTABLE.

Updated thru FAC 2001-27 (3/28/2005) http://www.fedbizopps.gov/

TABLE OF CONTENTS

Description …………………………………………................................................................. ……...3 Introduction ……………………………………………………… Scope ……………………………………………………… Research and Technical Objectives …………………… Reporting Requirements and Deliverables ……….................................................................…...14 Evaluation Factors for Award ……………………….................................................................…..18 Instructions, Conditions, and Notices to Offerors … ................................................................…26 Attachments ……………………………….……… ............................................................... ……..56

DESCRIPTION

You are invited to submit a proposal in accordance with the requirements of this Broad Agency Announcement (BAA- BARDA-08-08) entitled “Therapies for Hematopoietic Syndrome, Bone Marrow Stromal Cell Loss, and Vascular Injury Resulting From Acute Exposure to Ionizing Radiation”. This Broad Agency Announcement (BAA) is authorized by FAR 6.102(d)(2) and further described in FAR 35.016, Broad Agency Announcement. A BAA is a general announcement of an agency’s research and development interest. The intent of a BAA is to encourage the submission of creative and innovative approaches to specific research and development areas identified by the United States Government (USG).

A proposal submitted in response to this BAA must present a detailed technical and cost proposal designed to meet the Research and Technical Objectives described in this announcement. The proposal must be signed by an official authorized to contractually commit the submitting organization. The Statement of Work (SOW), including the specific work requirements and performance specifications, is developed and defined by the Offeror, not the USG. The SOW should not exceed ten (10) single spaced-pages (in 12 pt font, Times New Roman) in length within the technical proposal, which is limited to two hundred (200) pages total (including all appendices and attachments).

Proposals are not evaluated against a specific USG need, as in the case of a conventional Request for Proposal (RFP), since they are not submitted in accordance with a common SOW issued by the USG. Instead, Research and Technical Objectives are provided in the BAA that describe the research and development areas in which the USG is interested.

Proposals received as a result of the BAA are evaluated by a Technical Evaluation Panel (TEP) in accordance with the Evaluation Factors specified in the BAA. An Order of Merit Ranking is established by the Contracting Officer in lieu of a Competitive Range. Negotiations are conducted with those Offerors selected from the Order of Merit Ranking as set forth in this announcement under Evaluation Factors for Award.

At the conclusion of negotiations with the Offerors selected from the Order of Merit Ranking, those selected Offerors are allowed the opportunity to submit a Final Proposal Revision (FPR) to address weaknesses in the proposal based on issues identified by the TEP and to revise costs as may be appropriate. It is anticipated that multiple awards will result from this announcement and those awards will be multi-year, cost-reimbursement, completion type contracts. BARDA anticipates awarding 5-6 contracts. Awards are expected to be made on or about September 16, 2008. The HHS/BARDA estimates that the average annual total cost (direct and indirect cost combined) for these contracts will be $3 million to $5 million per contract. However, it is anticipated that the total cost for each award may vary depending upon the scope of the project and the technical objectives of the award. The length of time for which funding is requested should be consistent with the nature and complexity of the proposed research and development. The maximum period of performance is three (3) years.

The award document will be tailored in the final negotiations with the selected Offeror(s) and modified as appropriate for the type of Offeror organization, cost and/or fee arrangements, and other elements as negotiated prior to award.

INTRODUCTION

On December 19, 2006, President George W. Bush signed into law the Pandemic and All-Hazards Preparedness Act (Public Law 109-417), referred to as PAHPA. Title IV of PAHPA established the Biomedical Advanced Research and Development Authority (BARDA) in the Office of the Assistant Secretary for Preparedness and Response (ASPR) in the U.S. Department of Health and Human Services (HHS) to facilitate the research, development, and acquisition of medical countermeasures for chemical, biological, radiological, and nuclear (CBRN) agents and emerging infectious diseases, including pandemic influenza, that threaten the U.S. civilian population. BARDA encourages and facilitates the development and acquisition of medical countermeasures such as vaccines, therapeutics and diagnostics, as well as innovative approaches to meet the threat of CBRN agents and emerging infectious diseases, including pandemic influenza, in support of the mission and priorities of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) articulated in the PHEMCE implementation plan (http://www.hhs.gov/aspr/barda/phemce/enterprise/strategy/index.html). As part of its CBRN preparedness mission, BARDA announces a program to encourage advanced research and development aimed at medical countermeasures specifically addressing the hematopoietic and vascular syndromes resulting from acute exposure to ionizing radiation as from a potential bioterrorism act with radioactive materials or nuclear weapons. The increased threat of terrorism underscores the compelling need to develop improved treatments for protecting all segments of the civilian population, and specifically in this case, against radiation injury to the hematopoietic systems, especially neutropenia and thrombocytopenia, bone marrow progenitor cell and stromal cell loss, and vascular injury resulting from acute radiation injury.

HHS/ASPR/BARDA is using this BAA to advance the development of new therapeutics, including the development of new indications for already licensed therapeutics, as novel medical countermeasures for the treatment of large affected populations who are acutely exposed to ionizing radiation as a result of a nuclear detonation, radiologic dispersive device (RDD; such as a “dirty bomb”), or other radiologic mechanisms, including deliberate contamination.

Specifically, HHS/ASPR/BARDA seeks to acquire developed medical countermeasures that will be clinically useful in a civilian medical emergency situation that results from or involves exposure of a large population to the effects of a nuclear detonation, an RDD, or exposure to ionizing radiation/ radioactive material with or without combined injury or trauma. The purpose of this BAA, entitled “Therapies for Hematopoietic Syndrome, Bone Marrow Stromal Cell Loss, and Vascular Injury Resulting From Acute Exposure to Ionizing Radiation”, is to solicit proposals for research and development programs that focus on one or more of the following solicited research areas:

• Research and Development Area 1: the development of medical countermeasures that can replenish the normal hematopoietic profile, in whole or in part (i.e., treat neutropenia, lymphopenia and thrombocytopenia, etc.) following acute radiation exposure that induces lethal hematopoietic dyscrasias;

• Research and Development Area 2: development of medical countermeasures to replenish bone marrow niche and progenitor cells that normally populate the marrow stroma and niche environment and that can, following acute exposure to ionizing radiation that induces lethal hematopoietic dyscrasias, restore normal functioning hematopoietic cell lineages; or

• Research and Development Area 3: development of medical countermeasures that address injury to the vascular system induced following acute exposure to ionizing radiation, including changes in intimal integrity and clotting propensity, macrophage repair mechanisms and trafficking, vascular leak, endothelial repair, endovascular surface chemistry, alteration of angiogenesis, and other changes in anatomical or molecular pathology.

This BAA is to provide early development funding opportunities with the hope that some may progress sufficiently to allow BARDA the opportunity to acquire such products as medical countermeasures that can be approved by the Food and Drug Administration (FDA) to treat specific medical conditions resulting from exposure to ionizing radiation. It is therefore anticipated that research and development studies awarded from this BAA will advance therapeutic products toward eventual approval from the FDA for treatments of acute ionizing radiation injury affecting physiologic homeostasis of the hematopoietic and vascular systems.

Offerors are invited to submit proposals that request funding to advance the development of a promising therapeutic product that addresses one of the above three research and development areas. Offerors shall propose a well-defined product development path that must include completion of a Phase 1 clinical trial no later than three (3) years after contract award, unless Phase 1 is completed prior to contact award. The performance of studies in vertebrate animals and clinical studies must be consistent with all applicable Federal regulations and BARDA/NIH policies and guidelines for the conduct and oversight of research in vertebrate animals and human subjects. This announcement will also support post-Phase 1 product development activities in support of a New Drug Application (NDA) or a Biologic License Application (BLA), including:

1) Manufacturing scale-up supporting consistent lot-to-lot manufacturing.

2) Phase 2 clinical trials, if feasible and ethical.

3) Animal studies leading to pivotal animal efficacy studies required to support licensure under the U.S. Food and

Drug Administration (FDA) “Animal Rule” (21 CFR 314.600-314.650, 601.90-601.95).

BARDA is interested in the development of advanced (in clinical trials) therapeutic products with the potential to be approved or licensed for ARS treatment indication, and is particularly interested in the development of ARS indications for already-approved or licensed therapeutics. BARDA is also interested in the development of novel preclinical evaluation technologies, i.e., replacement of the nonhuman primate as the gold standard for radiation injury, and the development of radiation injury therapeutics formulated for long-term stability, high bioavailability, simple dosing regimens, and acceptable safety in diverse populations.

Note: Offerors proposing the clinical testing of drugs, biologics, or other treatments that are already in an advanced stage of product development for the indication of ionizing radiation exposure rescue, such as treatments presently or previously in clinical testing or the re-evaluation of existing treatments in the context of biodefense, are encouraged to consider whether their proposal would be more applicable to BARDA’s planned Request for Proposals entitled “Medical Countermeasures to Treat Neutropenia Arising as a Subset of the Hematologic Depression Resulting from Exposure to Ionizing Radiation“ which can be accessed at the FedBizOpps web site at http://www.FedBizOpps.gov or, for further information, at http://www.medicalcountermeasures.gov.

Offerors may submit a proposal that addresses more than one of the three research areas if the proposal focuses on the development of a single product. However, Offerors may submit a maximum of one drug/biologic per proposal per http://www.fedbizopps.gov/ http://www.medicalcountermeasures.gov/ research area.

It is anticipated that the majority of studies in each of these areas will involve animal models. These studies are expected to be supported using Institutional Animal Care and Use Committees (IACUC) as required by the US Department of Agriculture (USDA). Radiation exposure studies exceeding occupational limits in normal human subjects are considered unethical and thus surrogate animal models will be used for documentation of efficacy using the Animal Rule (21 CFR 314 and 601).

The following types of proposals are not responsive to this initiative:

The development of drugs or biologics intended solely for use prior to radiation exposure (prophylaxis), The development of drugs or biologics that must be administered within 24 hours of exposure to be effective, The development of next generation antibiotics and probiotics, blocking, decorporation, and purgative agents, antiemetics and other comfort or supportive measures, The development of therapeutics for the treatment of Gastrointestinal (GI) Syndrome, unless the therapy also addresses one or more of the research areas specifically addressed by the BAA, Proposals involving the development of animal models for mechanism discovery unless the models are directly relevant to the therapeutic product development, and, Phase 3 clinical trials.

Although the above mentioned research and development areas are not responsive to this announcement, they may be relevant to other BARDA or NIAID Biodefense research and development programs. A listing of such programs can be found on the BARDA web site http://www.hhs.gov/aspr/barda or the NIAID Biodefense funding website:

http://www2.niaid.nih.gov/biodefense/research/funding.htm.

BARDA reserves the right to award all or any portion of the Statement of Work proposed based on technical merit, programmatic balance and priorities, and the availability of funds. Furthermore, BARDA recognizes that product development is an iterative process and that the progress of a product through the development pathway requires ongoing evaluation to assess and reassess the likelihood for the product to meet the desired therapeutic objectives. Furthermore, BARDA reserves the right to determine, at any time during the contract period, that a particular candidate therapeutic has not demonstrated sufficient potential to merit further investment by BARDA in the development and evaluation of that product. BARDA, therefore, reserves the right to terminate the contract or make changes as permitted by the contract.

BARDA is aware that no single organization or institution may have the expertise and facilities required to perform all parts of their SOW. Therefore, it may be necessary for the Offeror to subcontract a portion of the work. The Offeror shall be responsible for all work performed under this contract including that performed by any subcontractor(s).

http://www.hhs.gov/aspr/barda http://www2.niaid.nih.gov/biodefense/research/funding.htm

SCOPE

It is anticipated that organizations selected under this BAA will have:

Identified a promising therapeutic

For the purposes of this BAA, a promising therapeutic is defined as a single agent that meets the following criteria.

a) A drug (synthetic or natural product) or a biological product intended for use in post-ionizing radiation exposure mitigation, or treatment of neutropenia, progenitor cell and/or niche stromal cell loss, or vascular injury resulting from acute radiation exposure, that is effective when administered not earlier than 24 hours post-exposure, and is the type of agent that is within the regulatory purview of either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA);

and,

b) A single agent with demonstrated therapeutic activity in an appropriate animal model for at least one of the three solicited Research and Development Areas. “Therapeutic activity in an appropriate animal model” is defined as the ability of a drug/biologic to provide a statistically and significantly better outcome (i.e. survival improvement) versus relevant controls under well-controlled and documented experimental conditions, and,

c) An agent for which an IND has been filed with FDA for any indication more than 30 days before the Offeror submits its Final Proposal Revision, provided that, at the time of submission of the Final Proposal Revision, FDA has not placed the IND on clinical hold.

Devised a Comprehensive Staged Product Development Plan

A Comprehensive Staged Product Development Plan is expected to summarize:

The intended use or indication of the proposed therapeutic product The intended product profile (strength, quality, purity and identity) The performance specifications and features of the therapeutic product that provide therapeutic benefit A description of the therapeutic product as it is currently configured A description and developmental status of the assays for product release which provide characterization, strength, identity, and purity, as well as any needed bioassays for biologic activity and efficacy.

Data to support the characterization and selection of the therapeutic product for further development. Specifically, a summary of data that demonstrates therapeutic activity in appropriate animal models and assays to address one of the three research and development areas. This includes: a detailed description of the assays and animal models, the radiation exposure (and method of radiation exposure standardization), rationale for the choice of animal model, as well as for the outcome/endpoints selected; documentation that the animal experiments were performed under well-controlled experimental conditions and data that support whether and how the therapeutic specifically addresses the research and development area.

Discussions with CDER or CBER (FDA) reviewers that are relevant to development activities for the proposed therapeutic product, including plans for developing data to support an Investigational New Drug (IND), BLA or NDA. (Note: It is strongly advised that Offerors seek guidance from the FDA regarding the Animal Rule 21 CFR 314 or 601 as a surrogate for clinical studies where the design may be unethical for inclusion of human subjects.)

BARDA recognizes that the regulatory path to licensure for the proposed therapeutics may not be well defined. The regulatory requirements are likely to be defined in an iterative decision-making process with the appropriate CDER/CBER authorities, based upon the ongoing review of the product during the advanced development process and as specific product-related data emerge. Despite the uncertainty of the development process, the Offeror(s) shall provide a Staged Product Development Plan (Critical Path) to approval or licensure based on current data and/or discussions with the appropriate FDA Division (CDER or CBER) recognizing risks and areas of significant uncertainty. Risk mitigation strategies shall be included.

Devised a Strategic Staged Product Development Plan A Strategic Staged Product Development Plan is expected to detail:

Activities and stages of product development that the Offeror is proposing to perform under contract funding.

Distinct stages of the product development pathway that are gates for Go/No Go decisions for advancing to the next stage of the Strategic Staged Product Development Plan.

The qualitative and quantitative criteria and accompanying data elements to be used to assess the scientific merit and technical feasibility of proceeding to the next stage of product development.

Milestones and timelines for the initiation, conduct, and completion of product development activities for each stage with a budget (in direct costs) linked to each stage.

If applicable, a description of product development platform technologies that are proposed to be employed within the Strategic Staged Product Development Plan. These technologies may address development timeframes and productivity, drug efficacy, specificity, safety and stability, delivery, etc. This description should clearly identify how the platform technologies will contribute to and improve the drug development process for the specific indication(s) proposed for development under this contract, as well as generally for other products.

Although it is the responsibility of the Offeror to propose a SOW, the types of product development activities that are within the scope of this BAA include:

Non-Clinical Research and Development Product development activities in this area include:

a) Evaluate the safety, pharmacokinetics/pharmacodynamics (PK/PD), bioavailability, solubility, formulation, dose, route and schedule of the therapeutic product in vitro and in animal models following Good Laboratory Practice guidelines (GLP: as defined in the U.S. Code of Federal Regulations – 21CFR 58).

b) Develop, characterize, and qualify and/or validate reagents and assays required for the clinical and non-clinical evaluation of the therapeutic product.

c) Conduct animal studies to support the evaluation of therapeutic products where efficacy cannot ethically be evaluated in humans. Animal models should be developed in the context of the anticipated indication for which the therapeutic product is being developed.

Manufacturing of Therapeutics Product development activities in this area include:

a) Develop a Drug Master File (DMF) or Biologics Master File (BB-MF) under current Good Manufacturing Practice guidelines (cGMP: as defined in the U.S. Code of Federal Regulations – 21CFR 314.420).

b) Process development for the manufacture of therapeutic product consistent with cGMP.

c) Manufacture of pilot lots of therapeutic product in amounts sufficient to carry out proposed non-clinical and clinical trials.

d) Formulation of Final Drug Product (FDP).

e) Preparation of and packaging of FDP.

f) Conduct of long-term stability studies of cGMP bulk and FDP.

Phase 1 Clinical Evaluation

a) Design a Phase 1 clinical trial to evaluate the safety and pharmacokinetics of the therapeutic product in humans.

b) Prepare and submit an IND application to the U.S. FDA.

c) Conduct a Phase 1 clinical trial in accordance with all federal guidelines, Good Clinical Practice guidelines (GCP:

as defined by 21 CFR 312 and ICH Guidelines document ICH E6 (http://www.pharmacontract.ch/support/su_ich_liste.htm). The Phase 1 clinical trial report is to follow the format of International Conference on Harmonization document ICH E3 “Guidelines on Structure and Content of Clinical Study Reports” (http://www.pharmacontract.ch/support/su_ich_liste.htm).

Post-Phase 1 NDA- or BLA-Supporting Activities

a) Conduct manufacturing scale-up supporting consistent lot-to-lot manufacturing of the therapeutic product.

b) Design and conduct a Phase 2 clinical trial, if ethical and feasible, in accordance with all Federal regulations and guidelines, Good Clinical Practice guidelines (GCP: as defined by 21 CFR 312 and ICH Guidelines document E6 (http://www.pharmacontract.ch/support/su_ich_liste.htm).

c) Contractor shall create a Target Product Profile (TPP) which will be further defined through discussion and negotiation with the Project Officer http://www.pharmacontract.ch/support/su_ich_liste.htm

RESEARCH AND TECHNICAL OBJECTIVES

Independently, and not as an agent of the USG, the Offeror shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the USG under the terms of this contract, as needed to provide the services delineated in the negotiated SOW. The specific components of the SOW and the scope of the product development activities to be undertaken will depend on the status of the individual therapeutic product as part of an overall Strategic Staged Product Development Plan, as well as regulatory requirements. The Offeror shall carry out activities within the contract SOW only as requested and approved by the Contracting Officer, and may not conduct work on the contract without prior approval from the Contracting Officer. Approval to carry out specific activities will be linked to approval by the Project Officer of the Strategic Staged Product Development Plan following contract award, approval of monthly and quarterly Progress Reports, review and approval of Clinical Trial Protocol(s) and supporting materials (see reporting requirements for a description of these reports).

The experimental objectives, approaches, methodology, possible outcomes and alternatives, as well as the personnel, percent of effort, specific duties, work location, supervision, lines of authority, and available equipment, facilities, and other resources should be described separately for each of the research areas. When preparing proposals in response to this BAA, the Offeror must follow the format described in Attachment 3 “Additional Technical Proposal Instructions.”

Offerors shall provide the following information for each proposal:

• Experimental Design. A detailed description of the experimental design (including the design of any human tissue sample studies), the rationale for experimental approaches, and a description of alternative approaches to be employed if these methods do not achieve the defined goals, is required.

• Project Plan and Milestones. The Comprehensive Staged Product Development Plan, i.e., Project Plan (Work Plan) shall include scientific, technical and administrative processes to achieve the goals of the contract. The Plan shall include milestones of the research and development program, including risk identification and mitigation, and time-line implementation of milestones. Milestones, and the expected timelines for achieving each milestone, will be used to assess progress in the product development of the medical countermeasure. The first year Work Plan shall be in sufficient detail to allow for monitoring the success of the research and development project over that interim. Years two and three may be less specific. Program Meetings (see below for description of Program Meetings) shall be incorporated into the Work Plan. An update to the Work Plan is required quarterly and will be part of the Quarterly Reports and the Annual Report.

• Strategic Staged Product Development The Offeror shall prepare and implement a Strategic Staged Product

Development Plan to advance the therapeutic product along a well-defined development path leading to a therapeutic product suitable for testing in humans in a Phase 1 clinical trial and/or for post-Phase 1 NDA- or BLA-enabling activities within the maximum three (3)-year period of the contract award. The Offeror shall perform all technical, regulatory, management, and administrative activities that are required to implement the Strategic Staged Product Development Plan. In addition, these efforts shall lead to the creation of the Target Product Profile (TPP), which shall be defined by the Project Officer.

Within fourteen (14) days of the effective date of the BAA award, the Offeror shall submit an updated Strategic Staged Product Development Plan and Work Plan. The Strategic Staged Product Development Plan and Work Plan shall be approved by the Project Officer and the Contracting Officer prior to initiation of any activities related to their implementation. The report shall contain:

a) Sufficient detail, documentation and analysis to support successful completion of the stage according to the predetermined qualitative and quantitative criteria that have been established for Go/No Go decision-making

b) Costs to complete the stage.

c) A description of the next stage of product development to be initiated, a revised Work Plan, if necessary, an updated budget and a request for approval to proceed to the next stage of product development.

In response to a need to change the Strategic Staged Product Development Plan (the Work Plan), the Offeror shall submit a Deviation Report. This report shall request a change in the agreed Work Plan and timelines. This report shall also include:

a) Discussion of the justification/rationale for the proposed change.

b) Options for addressing the needed changes from the approved timelines, including a cost-benefit analysis of each option.

c) Recommendations for the preferred option that includes a full analysis and discussion of the effect of the change on the entire product development program, timelines, and budget.

• Regulatory Compliance As required for the implementation of the Strategic Staged Product Development Plan, the

Offeror shall:

a) Be responsible for the regulatory aspects of the development and implementation of data management and quality control systems/procedures, including the transmission, storage, confidentiality, and retrieval of all study data.

b) Provide for the statistical design and analysis of data resulting from the research undertaken.

c) Provide raw data or specific analyses of data generated with contract funding to the Project Officer.

d) Ensure strict adherence to FDA regulations and guidance, including requirements for the conduct of animal studies and assays under GLP, the manufacturing of the therapeutic product under cGMP, and the conduct of clinical trials under GCP standards. The Offeror shall maintain quality assurance documentation to support adherence in these areas.

e) Arrange for independent audits, as needed or as requested by the Project Officer and as concurred by the Contracting Officer. Audits may be requested to assure that Offeror and/or sub-Offeror facilities and all planned procedures comply with the FDA regulations and guidance that are required to meet GLP, cGMP and GCP standards. In addition, the Offeror shall ensure that all Offeror and/or sub-Offeror records and staff are available for site visits or audits. The Offeror shall provide interim and final audit reports to the Project Officer and the Contracting Officer within thirty (30) calendar days of the completion of the audit. BARDA reserves the right to conduct independent audits of the Offeror and its sub-Offerors as needed to evaluate compliance with the FDA regulations and guidance, including those required to meet GLP, cGMP or GCP standards. Such audits may also be conducted prior to contract award as a part of the technical evaluation of the Offerors’ Technical Proposal.

f) Comply with FDA regulations and guidance for preparation, format, and submission of all regulatory documents to the FDA.

g) Comply with the NIH Guidelines for Research Involving Recombinant DNA molecules.

h) Provide data-extractable electronic media copies of all contract-generated regulatory documents to BARDA.

• Radiation Controls and Safety The Offeror must describe the conditions of use and disposal of radioactive materials anticipated to be used in any of the BAA funded activities as well as operational safety, controls and standardization of devices used for radiation measurement and exposure. The Offeror shall provide evidence of Federal, State and Local health and safety regulatory compliance as well as evidence of holding appropriate institutional license(s) from regulatory authorities and documentation of oversight from a Radiation Safety Committee. This shall also be required of all subcontracted work.

• Animal Model Studies. The rationale for proposed animal model studies and a detailed description of their relevance to human radiation injury shall be provided. Offerors proposing an animal model shall comply with all required guidelines for animal welfare. BARDA currently uses the guidelines employed at NIH as found in:

http://grants1.nih.gov/grants/funding/phs398/section_1.html#f_vertebrate_animals. An approved Plan for animal care and use is required of all Offerors and each must provide evidence of an ongoing and active Institutional Animal Care and Use Committee (IACUC) with USDA oversight of the facilities. AAALAC certification is a plus.

• Care of Vertebrate Animals

a) Before undertaking performance of any contract involving research on live, vertebrate animals, the Contractor shall register with the Secretary of Agriculture of the United Sates in accordance with 7 U.S.C. 2316 and 9 CFR Section

2.30. The Contractor shall furnish evidence of such registration to the Contracting Officer.

b) The Contractor shall acquire animals used in research from a dealer licensed by the Secretary of Agriculture under

7. U.S.C. 2131-2157 and 9 CFR Sections 2.1-2.11, or from a source that is exempt from licensing under those sections.

c) The Contractor agrees that all research involving live, vertebrate animals shall be conducted in accordance with applicable local, state, federal (including 21 CFR 58), or other regulations and policy on humane care and use of laboratory animals.

d) If at any time during performance of this contract, the Contracting Officer determines that the Contractor is not in compliance with any of the requirements and/or standards stated in paragraphs (a) through (c) above, the http://grants1.nih.gov/grants/funding/phs398/section_1.html#f_vertebrate_animals

Contracting Officer may immediately suspend, in whole or in part, work and further payments under this contract until the Contractor corrects the noncompliance. Notice of the suspension may be communicated by telephone and confirmed in writing. If the Contractor fails to complete corrective action within the period of time designated in the Contracting Officer’s written notice of suspension, the Contracting Officer may terminate this contract in whole or in part.

• Data Management. Data created from this contract shall be stored and managed at the Offerors’ site in a Laboratory

Management System controlled and maintained by the Offeror, in consultation with the Project Officer. The Database Management System (DMS) shall be commercially available, documented, and supported by a relational database management system.

• Security Systems and Security Plan. The Offeror shall provide security systems, firewalls, and computer virus detection systems to be used to ensure database integrity and security. The local database at each Offeror site will contain, at a minimum: a) raw data and original results, and, b) detailed experimental protocols. To ensure database integrity and interoperability, the Offeror shall include bioinformatics experts, in consultation with and approved by the Project Officer, in the research and development team. Key bioinformatics team members shall participate in the annual meetings (described below) in special sessions to define and execute standard operating procedures (SOPs) for data management and analysis. Additionally, during the life of the contract, the Offeror may be required to submit data to a centralized database developed and maintained by BARDA information technology personnel. After contract award, the Project Officer and a BARDA-IT representative will work with the successful Offeror(s) to develop a process for data submission to the BARDA-IT maintained database.

• Clinical Studies and Associated Clinical Trials

a) Human Subjects

Research involving human subjects shall be conducted in accordance with FDA's regulations governing INDs and human subject research, and shall not be conducted under the contract until the protocol has been approved by HHS, written notice of such approval has been provided by the Contracting Officer, and the Contractor has provided to the Contracting Officer a properly completed "Protection of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption", Form OMB No. 0990-0263 (formerly Optional Form 310) certifying IRB review and approval of the protocol. The human subject certification can be met by submission of the Contractor's self designated form, provided that it contains the information required by the "Protection of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption", Form OMB No. 0990-0263 (formerly Optional Form 310).

When research involving Human Subjects will take place at collaborating sites or other performance sites, the Contractor shall obtain, and keep on file, a properly completed "Protection of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption", Form OMB No. 0990-0263 (formerly Optional Form 310) certifying IRB review and approval of the research.

b) Protection of Human Subjects

i. No contract involving human subjects research shall be awarded until acceptable assurance has been given that the project or activity will be subject to initial and continuing review by an appropriate institutional review committee(s) as described in 45 CFR Part 46. Contracts involving human subjects will not be awarded to an individual unless the individual is affiliated with or sponsored by an institution has an Office for Human Research Protections (OHRP) approved assurance of compliance in place and will assume responsibility for safeguarding the human subjects involved. The OHRP web site is: http://www.hhs.gov/ohrp. The Offeror further agrees to provide certification at least annually that the institutional review board (IRB) has reviewed and approved the procedures which involve human subjects in accordance with 45 CFR Part 46 and the Assurance of Compliance.

ii. The Offeror shall bear full responsibility for the performance of all work and services involving the use of human subjects under this contract in a proper manner and as safely as is feasible. The parties hereto agree that the Offeror retains the right to control and direct the performance of all work under this contract. Nothing in this contract shall be deemed to constitute the Offeror or any subcontractor, agent or employee of the Offeror, or any other person, organization, institution, or group of any kind whatsoever, as the agent or employee of the Government. The Offeror agrees that it has entered into this contract and will discharge its obligations, duties, and undertakings and the work pursuant thereto, whether requiring professional judgment or otherwise, as an independent Offeror without imputing liability on the part of the Government for the acts of the Offeror or its employees.

http://www.hhs.gov/ohrp

iii. If at any time during performance of this contract, the Contracting Officer determines, in consultation with the OHRP, that the Offeror is not in compliance with any of the requirements and/or standards stated in paragraphs (a) and (b) above, the Contracting Officer may immediately suspend, in whole or in part, work and further payments under the contract until the Offeror corrects such noncompliance. Notice of the suspension may be communicated by telephone and confirmed in writing.

iv. If the Offeror fails to complete corrective action within the period of time designated in the Contracting Officer’s written notice of suspension, the Contracting Officer may, in consultation with OHRP, terminate the contract in whole or in part, and the Offeror’s name may be removed from the list of those Offerors with approved Health and Human Services Human Subject Assurances.

c) Offeror Requirements

i. Comply with all Federal and HHS Clinical Terms of Award, BARDA’s Clinical Terms of Award mirror those of NIAID (http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf).

ii. Prior to study initiation (or subsequently with respect to amendments), submit to the BARDA Project Officer, for review and approval by the appropriate BARDA review committee, all clinical trial protocols and supporting documentation (e.g., sample informed consent forms, Investigators Brochure (s) (IB), case report forms, manuals of procedures, site quality management plan, data management plan, safety oversight plan and local Institutional Review Board committee approvals). Monitoring Plans are subject to approval by the Project Officer.

iii. Obtain final approval of all anticipated clinical protocols from the Project Officer prior to submission of an FDA IND, and prior to any trial’s participant enrollment.

iv. Serve as the Product Sponsor with responsibility for:

• Preparing materials for, and request, schedule, and participate in all meetings with the FDA (CDER/CBER), including meetings to review IND, NDA, and BLA packages.

• Submitting all documentation to the FDA in a timely manner, consistent with timelines set out in the contract and by the FDA.

• Including BARDA staff, as designated by the Project Officer, in meetings and teleconferences with the FDA.

• Providing copies of all FDA correspondence and meeting minutes that are relevant to the therapeutic product to the BARDA Project Officer.

Although Phase 3 clinical trials will not be funded under this program, the IRB-approved protocol(s) and the Investigators’ Brochure(s) (IB) for any parent or core clinical trial(s), e.g., a source for data or materials for the proposed studies, shall be included with the proposal as part of the human subjects section. Drafts of proposed clinical trial informed consent form(s), if available at the time of the proposal submission, should be included as examples.

In order to ensure coordination between the proposed studies and any parent or core clinical trial(s), the Offeror of the parent or core clinical trial (note: often referred to as “Sponsor”) shall have a written agreement regarding the conduct of the studies presented in this proposal. Prior to award, the Offeror shall provide to BARDA a “Memorandum of Understanding” signed by the Offeror, an appropriate representative of the applicant institution, the principal investigator of the parent or core clinical site, or core clinical trial site(s), and an appropriate representative of the Offeror attending to the parent or core clinical trial site(s). The Memorandum shall outline the specifics of the agreement between the parties with respect to the following areas:

i. Nature of the biological specimens and the access controls;

ii. Timing and manner of access to data produced by the parent or core clinical trial site(s) that will be used in the proposed studies, including procedures for the prevention of unblinding of the parent trial should blinding be required;

iii. Ownership, analysis, and release of data resulting from the proposed studies;

iv. Documentation of quality assurance procedures for both the parent trial and the proposed studies;

v. Documentation of data and safety monitoring procedures for the parent trial, especially for efficacy trials;

vi. Ownership of intellectual property developed during the proposed studies; and

vii. Publication of the results of the proposed studies.

d) Human Materials. Descriptions of any human tissue and/or clinical samples or data to be used in the proposed studies, including how human subjects shall be protected from research risks and justification for the ethnic, gender, and age compositions of the human populations chosen for analysis, is required. BARDA is utilizing and requiring compliance with all NIH guidelines for human subjects research as found in:

http://grants1.nih.gov/grants/funding/phs398/section_1.html#e_humansubs. Descriptions of human use shall be http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf sufficiently detailed to allow the Technical Evaluation Panel to determine the feasibility and appropriateness of the proposed experimental approaches.

It is understood that the acquisition and supply of all human specimen material (including fetal material) used under the resultant contract will be obtained by the Contractor in full compliance with applicable Federal, State and Local laws and the provisions of the Uniform Anatomical Gift Act in the United States and that no undue inducements, monetary or otherwise, will be offered to any person to influence their donation of human material.

• Scientific, Technical, Management and Administrative Team The Offeror shall provide all expertise needed for the implementation of the Strategic Staged Product Development Plan to be performed under the contract, including:

research, manufacturing, regulatory, clinical, statistical, management, and administrative activities. The Offerors’ team must include strong scientific leadership, as well as experience and expertise in the management, design and execution of a research and development program focused on product development, manufacturing, and testing in humans and in vertebrate animals. The Principal Investigator (PI) shall be responsible for all aspects of project performance and communication with the Project Officer and the Contracting Officer. In addition, the Offeror shall provide a Project Manager who is responsible for the day-to-day monitoring and tracking of progress and timelines, the coordination of project activities and costs incurred.

• Facilities, Equipment and other Resources The Offeror shall provide the equipment, facilities, training and other resources required to implement the SOW and the Strategic Staged Product Development Plan in compliance with all Federal regulations. Depending on the stage of development of the therapeutic product, this may include:

a) The performance of IND-enabling assays and animal studies under GLP.

b) Production, characterization and release testing of therapeutic agent under cGMP conditions.

c) Performance of clinical trial(s) in humans under GCP.

d) The humane care and use of vertebrate animals with IACUC and USDA oversight

e) The handling, storing and shipping of radioactive agents and radiologic devices. In terms of radiologic operations, BARDA expects operational standards for handling radioactive material, radiologic devices and radioactive waste to be managed under environmental health and safety practices that follow, for example, the guidance of the Department of Energy’s Lawrence Berkeley Laboratory Environmental Health and Safety Publication 3000 (http://www.lbl.gov/ehs/pub3000/CH21.html#_Toc407168416) as well as relevant Federal, State and local laws.

f) The handling and disposal of potentially dangerous biological and chemical agents. These activities shall require Biosafety practices and procedures as described in Biosafety in Microbiology and Biomedical Laboratories, 4th ed., which is available at: http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm. In addition, and if the Offerors propose using Select Agents as named by the Centers for Disease Control and Prevention (CDC) Select Agent Program, the Offerors shall refer to: http://www.cdc.gov/od/sap.

The Offeror is required to undertake all studies with documentation of approvals from all Institutional biosafety, radiologic and animal oversight committees. At the request of the Project Officer, the Offeror shall provide copies of all notes, letters and materials submitted to and from all such committee reviews. Documentation of all approvals of experiments, protocols and procedures shall be copied and forwarded to the Project Officer for retention in the Project File at BARDA.

• Possession, Use and Transfer of Select Agents or Toxins. The contractor will not conduct any work involving Select

Agents or toxins under this contract until the contractor and any associated subcontractor(s) comply with the following requirements:

a) For prime or subcontract awards to US companies or institutions that will possess, use, and/or transfer Select Agents under this contract: The prime and/or subcontractor must comply with the provisions of 42 CFR Part 73, 7 CFR Part 331, and/or 9 CFR Part 121, as required, before using BARDA funds for any work involving Select Agents.