Contracting
Office Address
Other Defense Agencies, Defense Advanced Research Projects Agency, Contracts
Management Office, 3701 North Fairfax Drive, Arlington, VA, 22203-1714
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 teams 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
Point of Contact
Barbara McQuiston, Deputy Director, DSO, Phone 703-526-4759, Fax 703-248-1916,
Email Barbara.McQuiston@darpa.mil
