MODIFICATION
A -- DEFENSE SCIENCES RESEARCH AND TECHNOLOGY
- Notice Date
- 7/2/2007
- Notice Type
- Modification
- NAICS
- 541710
— Research and Development in the Physical, Engineering, and Life Sciences
- Contracting Office
- Other Defense Agencies, Defense Advanced Research Projects Agency, Contracts Management Office, 3701 North Fairfax Drive, Arlington, VA, 22203-1714, UNITED STATES
- ZIP Code
- 00000
- Solicitation Number
- BAA07-21
- Response Due
- 2/14/2008
- Archive Date
- 2/29/2008
- Description
- BLOOD PHARMING SOL, BAA 07-21, Addendum 5, White Papers Due: 4:00PM ET, August 6, 2007; Full Proposals Due: 4:00PM ET, October 1, 2007; Technical POC: Dr. Jon Mogford, Program Manager, DARPA/DSO; Ph: (571) 218-4928; Email: BAA07-21@darpa.mil; URL: http://www.darpa.mil/dso/solicitations/solicit.htm; Website Submission: http://www.sainc.com/dsobaa/ DESCRIPTION (Note: This BAA Addendum 5 is submitted as a Special Focus Area, as described in the original BAA, 07-21.) The Defense Sciences Office seeks innovative proposals to develop the science and technology necessary to enable in-theatre production of red blood cells (RBCs) from a progenitor cell source thus replacing the current system of donor blood. The vision for the Blood Pharming Program is to develop novel technologies to enable in vitro production of red blood cells that are untainted, readily available, and free of storage lesions. The ultimate goal of the program is the development of an automated, fieldable cell culture and packaging system capable of producing transfusable amounts of universal donor (Type O negative) RBCs using human progenitor cells as starting material. RBCs produced by the system must be shown to be the functional equivalent of donor-derived RBCs and induce no greater responses than normal donor derived RBCs. Submissions must provide evidence of a highly integrated, multi-disciplinary team led by a Systems Integrator (SI) capable of fulfilling the vision, objectives and milestones of the program as detailed herein. The final product will be an automated culture system that 1) maintains a self-renewing progenitor cell population, 2) supports the differentiation, separation and packaging of transfusable RBCs, and 3) is ready for submission to the U.S. Food and Drug Administration (FDA) for all applicable device and transfusable cell product approvals. This effort will be conducted over a 36-month period in three phases. Proposers are requested to submit a proposal focused on addressing the Phase 1 milestone and metrics and describe how the approach will transition to the subsequent phases. BACKGROUND Transfusion therapy has been an integral part of military medicine since the middle of the last century. As the O2-carrying component of blood, RBCs are the most transfused blood product in battlefield trauma care. Unfortunately, it is likely that fresh RBCs are either unavailable or limited in supply in a battlefield environment due to the inherent liabilities of the donor system (e.g., recruitment challenges, increasing deferment criteria) coupled with the global nature of U.S. military operations. In addition, well-documented changes occur to RBCs during ex vivo storage that affect normal function and may be detrimental to the recipient. In the seriously injured warfighter, such ?storage-induced lesions? may compound the physiologically stressful effects of trauma by induction of inflammatory and/or immunologic responses. The purpose of the Blood Pharming Program is to overcome these problems by creating an automated culture and packaging system that will yield a donorless supply of universal donor RBCs from progenitor cell sources in theater. In order to achieve the program goals, several significant technical challenges in the fields of cell biology, bioreactor capability, and design must be overcome. For example, it has been shown that mature, functional RBCs can be derived from a number of different progenitor cell types including those derived from bone marrow, cord blood, apheresed blood, etc. However, large-scale production of transfusable RBCs has not been achieved regardless of the progenitor cell source to date. In addition, it is imperative that RBCs produced by the progenitor-based system be functionally equivalent to fresh donor cells especially with regard to O2-carrying capacity and morphology. Separately, an automated cell culture system capable of a) maintaining a self-renewing progenitor population, b) providing a milieu for efficient differentiation along the erythroid pathway, c) sorting/purifying end-product RBCs, and d) packaging RBCs in a ?ready for transfusion? manner does not exist. It is envisioned that the automated culture/packaging system will be placed in military medical treatment facilities, and therefore must operate under field conditions and with minimal user intervention. To achieve these goals, revolutionary advances in research areas such as control of progenitor cell expansion/differentiation and development of automated bioreactor systems that are capable of automated cell manipulation and cell purification will be necessary. PROGRAM GOALS AND MILESTONES The Blood Pharming Program is a 36-month thrust to deliver a fully integrated RBC production system and the protocols enabling large-scale production of transfusable RBCs. The program is comprehensive and will deliver a system that is sufficiently mature to enter the appropriate FDA approval processes for general medical use. This will be an extremely aggressive, milestone-driven program. Consequently, it is necessary that progress be assessed regularly throughout the program via scheduled milestones and metrics associated with the performance of critical components. This program will be divided into three major phases (9-month Phase I, 18-month Phase II and a 9-month Phase III). It is understood that research in many areas will be required in order to reach the ultimate goal. These research areas will include, but are not limited to: progenitor cell biology and erythroid differentiation; RBC physiology; cellular support matrices/scaffolds; automated cell culture systems; and cell sorting, purification and packaging. Achievement of program milestones/metrics will demand prompt identification of areas requiring further research and rapid application of advancements made in these areas. Proposers must detail the critical steps for progenitor cell maintenance and erythroid differentiation, as well as the components necessary to construct an automated RBC production and packaging system and address how their collective team will achieve those challenges. Successful Phase I teams will demonstrate production of 10 Units of universal donor RBCs per week for 4 weeks in an automated culture system using a non-self-renewing (replaceable) progenitor cell population. For the realization of this milestone, research efforts should: 1) Demonstrate at least 2x106-fold expansion from progenitor source to mature RBCs, 2) Identify at least 3 stage-specific cell properties (size, shape, biomarker expression) that support automated culture, and 3) Demonstrate normal RBC properties and function including, but not limited to: Blood Type: O negative Morphologic Characteristics: Size 7-8 micrometers, Biconcave Disc, Loss of organelles Mean Corpuscular Hemoglobin Concentration: 32 to 36 g/dl Mean Corpuscular Volume: 80 - 100 fL Mean Corpuscular Hemoglobin: 29 - 31 pg/cell Loss of Progenitor Markers: CD34, c-kit, Sca-1, CD133, CD38, CD71 (specific markers for the chosen progenitor cell source should be provided) Expression of RBC Markers: Lin, LDS staining Deformability: DI max 0.41 to 0.53 Enzymatic Activity: Glucose-6-phosphate dehydrogenase (G6PD) 8.6-18.6 IU/g hemoglobin, Pyruvate Kinase (PK) 2.0-8.8 IU/g hemoglobin Oxygen equilibrium measurements; Kinetics of CO2 Rebinding: log(P50) value 1.3, N50 2.29; Two phases corresponding to R and T states Inflammatory/Immunogenic Markers: Pyrogen- and pathogen-free; in vitro absence of immuno-inflammatory response (e.g., mixed lymphocyte culture assay) Successful Phase II teams will demonstrate production of 100 Units of universal donor RBCs per week for 8 weeks in an automated culture system using a self-renewing (not replaceable) progenitor population. For the realization of this milestone, research efforts must: 1) Maintain Phase I cellular product, 2) Demonstrate at least 2x108-fold expansion of progenitor population to mature RBCs, and 3) Prepare and submit all applicable FDA documentation for the cell production system and for a transfusable blood product. Successful Phase III teams will develop a fieldable, RBC production system less than or equal to a 47 ft3 total dimension. For the realization of this milestone, research efforts must: 1) Maintain Phase 2 metrics, and 2) Have a production system that meets current military specifications for use in an in-theater medical treatment facility including the ability to withstand extremes of temperature, humidity, dust, frequent transport, and electrical transients. TEAM ORGANIZATION The goals of the Blood Pharming Program demand that a central element of the successful proposal will be a multi-disciplinary team with demonstrated capability. Involved fields of expertise should include progenitor cell biologists, cell culture experts, bioreactor engineers, cell separation scientists, clinicians, and experience with product commercialization and with the FDA regulatory environment. Proposals that center solely on one research area, while neglecting the overall vision, will not be considered for funding. It is critical that the research team be built from its inception around a Systems Integrator (SI). The SI will be responsible for the overall team direction, organization, and accomplishment of all milestones and the delivery of the final product, including the FDA approval application. Consequently, the SI must have a proven record of success in integration efforts of similar complexity, as well as a commitment to shepherd the program to commercial transition. The SI must demonstrate complete understanding and sharing of the DARPA vision of an automated production system to create a donorless source of universal donor RBCs that is ultimately fieldable; the SI that is strictly in the effort for project management will not be successful. As the team leader held accountable for timely delivery of the proposed work, the SI must have the authority to develop and maintain the proper team membership to ensure accomplishment of the task. During the course of performance, it is expected that some team members may be more active than others and that some team members may need to be replaced. PROPOSAL SUBMISSION A two-stage source selection is anticipated. It is STRONGLY ENCOURAGED that a white paper be submitted prior to full proposal submission, according to the guidelines provided below. White Paper and Full Proposal Deadlines White papers will be accepted until August 6, 2007, NO LATER THAN 4:00PM ET. All white papers will be reviewed no later than August 27, 2007 and recommendations for full proposals will be provided at that time. Full proposals will be due October 1, 2007, NO LATER THAN 4:00PM ET. White papers and proposals submitted by fax will not be accepted. All full proposal submissions will be evaluated regardless of the disposition of the white paper. Note that a full proposal may be submitted at any time before the close of the solicitation without having submitted a white paper. White Paper Submission Guidelines White papers of 8 pages or less (not counting cover sheet) will be reviewed for the purpose of recommending the submission of full proposals. The white paper must include the following sections: 1) A cover sheet that includes the Technical Point of Contact's information (salutation, name, address, phone, fax, email, lead organization and business type), the title of the proposed work, the estimated cost, and the duration (in months) of the proposed work. (Note: cover sheet does not count towards page limit.) 2) An executive summary, including a clear statement of the uniqueness of the idea. DSO is looking for ideas that will revolutionize advances in progenitor cell expansion, their efficient differentiation and the development of automated bioreactor systems capable of automated cell manipulation and purification. 3) A concise statement of the approach to the problem, the scientific and technical challenges inherent in this approach, and possible solutions for overcoming potential problems. This statement will also serve to demonstrate an understanding of the state-of-the-art in the field. 4) An analysis of the changes in current state-of-the-art approaches necessary to achieve the goals of this program. 5) Timelines and milestone achievements by which progress can be measured. These timelines and milestones should be as detailed as possible. Milestones must be associated with demonstrable metrics. 6) A cost estimate for resources over the proposed timeline. This cost estimate should include both labor and materials costs. 7) A summary of expertise of the key personnel on the project relevant to the program goals. The SI should be identified, and if the team is multi-organizational, a proposed management structure should be included. 8) Brief list of relevant references. Full Proposal Submission Guidelines As described in BAA 07-21, full proposals shall consist of two volumes: Technical and Cost. Follow the general guidelines for full proposal format and content provided at: http://www.darpa.mil/baa/BAA07-21pt2.html. Each technical proposal must have a clearly defined, multi-disciplined research team and management approach. The research team must incorporate people with expertise in all appropriate research areas listed above, and the proposal must clearly define how the team will work together to achieve the program goals. One of the team members must be designated as the SI. The SI will be responsible for coordinating the team and demonstrating the project milestones. Proposals that address only a subset of the research areas listed above or do not contain a clear indication of the management approach may not be considered for funding. In addition to the sections specified in the BAA announcement, the technical volume of the research proposal must also contain the following information (limited to a maximum of 25 pages): 1) Technical Approach: Clearly outline the scientific and technical approaches for achieving the Phase I milestones listed above. Specific technical challenges may include, but are not limited to: a) Determination of the most appropriate and available type of progenitor cell source based on availability, genetic stability and efficiency of RBC production, b) Optimization of culture conditions for maintenance of a self-renewing progenitor population while driving a subset of cells into erythroid differentiation, c) Development of strategies to control RBC antigen presentation, d) Development of Good Manufacturing Practices (GMP)-compliant automated cell culture systems, and e) Development of methods to adequately preserve starting progenitor cell stocks and matured RBCs. Obstacles inherent in addressing the Phase I milestones and solutions for overcoming potential problems should be provided. In addition, a list of smaller project accomplishments that should occur to meet the Phase I milestones should be listed. All technical descriptions should be grouped into the research areas relevant to achieving the Phase I goals. 2) Research Team: Clearly define the capabilities of the SI and individual team members and how their expertise relates to the research areas defined in the technical approach. 3) Phase Transition: Succinctly detail the team?s vision for transition to subsequent program phases. This should include how the chosen technical approaches will be expanded to address Phase II and III milestones described above. EVALUATION OF PROPOSALS Evaluation of the proposals will be in accordance with BAA 07-21. For general administrative questions, please refer to the original FEDBIZOPPS solicitation, BAA 07-21, of February 14, 2007: http://www.darpa.mil/dso/solicitations/solicit.htm. Web address for Proposal Submission: http://www.sainc.com/dsobaa/. Address for White Paper and Full Proposal Submission: DARPA/DSO ATTN: BAA 07-21, Addendum 5 3701 North Fairfax Drive Arlington, VA 22203-1714 Email Address: BAA07-21@darpa.mil General Information In all correspondence, reference BAA 07-21, Addendum 5. Technical Point of Contact Dr. Jon Mogford, Program Manager, DARPA/DSO; Phone: (571) 218-4928; Email: jon.mogford@darpa.mil
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