Contracting Office Address

Other Defense Agencies, Defense Advanced Research Projects Agency, Contracts Management Office, 3701 North Fairfax Drive, Arlington, VA, 22203-1714

Description

Special Focus Area:
FEEDBACK REGULATED AUTOMATIC MOLECULAR RELEASE (FRAMR) SOL BAA 06-19, Addendum 5, DUE: 12/14/06. TECHNICAL POC: Dr. Donald J. Leo, DARPA/DSO, Ph: (571) 218-4939, Email: baa06-19@darpa.mil; URL: www.darpa.mil/dso. Website Submission: http://www.sainc.com/dso0619/


DESCRIPTION

(Note: This BAA Addendum 5 is submitted as a Special Focus Area as described in the original BAA 06-19.)

As part of a larger program to mitigate pain due to battlefield trauma and improve soldier self care, DARPA seeks innovative proposals for the development of biodegradable self-regulating drug delivery systems that enable feedback-regulated release in response to biomarker(s) correlated with drug toxicity. These systems will enable new means of soldier self-care through the development of drug delivery methods that guarantee, in the combat environment, the delivery of a therapeutic dose while eliminating the possibility of harmful side effects through drug overdosage. This problem is unique to the military due to the need for effective therapeutics that can be administered quickly and safely to soldiers who may be suffering from a wide range of trauma in an uncontrolled battlefield environment.

Proposals are requested for research projects that will develop feedback-regulated drug delivery systems that, like the released drug, are eliminated from the body by normal pathways of metabolism and excretion without toxic effects. Of greatest relevance to battlefield use are delivery systems for one or more of the classes of Food and Drug Administration-approved therapeutics (general anesthetics, local anesthetics, narcotics, or analgesics) that are currently used in tactical field care or battlefield medicine. The system might also be designed to release pharmacological or physiological antagonists in response to agonist-induced toxicities. It is also envisioned that the drug delivery systems can be administered by untrained personnel or self-administered with little regard for actual dosage, and that the route(s) of administration be suitable for conscious and unconscious patients. The duration of therapeutic effect must be at least as long as that seen with conventional formulations.

The critical thrust of the FRAMR Program is to develop a drug release system that is modulated by one or more plasma biomarkers correlated to the toxic effect of the drug. That is, the delivery system will shut off the release of the drug when a biomarker correlated with a toxic effect of the drug is present. A complementary strategy might be to release a pharmacological or physiological antagonist to reverse toxic effects or decrease the effective agonist concentration when a biomarker correlated to toxic effect is present.

Proposals are requested for integrated drug delivery systems that utilize feedback control. Systems that rely only on site-specific targeting, contain non-biodegradable or toxic components, or non-feedback controlled (open loop) technologies will not be considered for funding. Systems that require external energy sources to modulate release or ancillary devices to facilitate or effect administration will also not be considered. Furthermore, this program will not support the development or improvement of therapeutics, only the development of new drug delivery systems that have relevance to tactical field care or battlefield medicine.

It is expected that each research effort will consist of an interdisciplinary team with sufficient expertise and experience to develop a feedback-regulated drug delivery system and characterize its in vitro performance. Arguments for the feasibility and performance of the proposed system should be soundly based in pharmacokinetic and pharmacodynamic principles.

BACKGROUND
Drugs that ameliorate pain from surgery or trauma are widely used in battlefield medicine and tactical field care. In the hands of trained professionals, powerful analgesics such as morphine can be safely titrated to therapeutic effect while minimizing adverse drug effects. General anesthetics are also widely used, but require sophisticated expertise and equipment for safe use. On the battlefield, however, resources and equipment might be strained or unavailable, especially at the tactical level where combatants and medics are limited by what they can carry. Trained medics can administer drugs such as morphine, while in some cases non-medically trained combatants or the wounded himself must administer powerful drugs. Under these extreme conditions, careful titration of drug dosage to assure pain control is impractical if not impossible, while the risk of unintentional overdosage might be significant. For these reasons, the Department of Defense is interested in drug dosage systems that with a single dose would self-titrate to optimal therapeutic dose or maximal therapeutic effect while at the same time minimizing drug adverse events. Such systems must be suitable for conscious or unconscious patients and be simple to administer or self-administer without supplemental equipment. In addition to their immediate value at the tactical level, a self-regulating delivery system would extend and enlarge the military's capabilities for providing safe general anesthesia for surgical procedures.

The concept of a self-regulating drug delivery system has been limited almost exclusively to glucose-sensitive systems that regulate their release of insulin. No self-regulating system has reached the market, however, while significant resources have been devoted to "open-loop" systems (typically liposomal or polymeric) that provide sustained drug release. While these systems are valuable and widely used, they are unable to regulate drug release in response to environmental cues. In contrast, the FRAMR Program will develop "closed-loop" drug delivery systems that rely on feedback from biomarkers to ensure that the plasma drug concentration is within its therapeutic range. Such a system will revolutionize battlefield care.

PHASE I DURATION, GOALS, AND MILESTONES
DARPA seeks proposals for a Phase I program with a duration not exceeding twelve months. The goal of the Phase I Program is an in vitro demonstration of feedback-regulated drug delivery in response to changes in biomarkers correlated to toxic effect.

The Phase I milestones are:

1. Demonstrate that the release rate of the drug in the drug delivery system is sufficient to achieve therapeutic levels. This demonstration must consist of an in vitro measurement of drug release.
2. Demonstration that the release rate of the drug can be reduced by an amount sufficient to avoid toxicity (e.g. > 10:1) in the presence of a biomarker correlated to a toxic effect associated with battlefield trauma. This demonstration must consist of an in vitro measurement of drug release in the presence of physiological concentrations of biomarker correlated with toxic effect.
3. Demonstrate that the drug delivery system is non-toxic to cell cultures. Toxicological testing should be consistent with published FDA guidance on toxicological and preclinical testing required for Investigational New Drug (IND) submission. It is not expected that all preclinical testing will be accomplished during Phase I, only that evidence is obtained to support further experimentation and advancement to Phase II.

Note that there will be no human or animal testing allowed in the Phase I program.

PHASE II RESEARCH GOALS
Successful Phase I projects may be considered for follow-on Phase II funding to continue development of the feedback-regulated drug release system. Components of the Phase II research will include demonstration that the drug delivery system can be stored for a sufficient period of time (e.g. 3 months) and in vivo tests of the system on a small animal model.

WHITE PAPER GUIDELINES
It is STRONGLY ENCOURAGED that a white paper be submitted to determine the acceptability of the proposed concept to the Broad Agency Announcement. The white paper should be of no more than 8 pages and should contain the following sections:

a. Definition of Battlefield Therapeutic: Define a battlefield general anesthetic, local anesthetic, narcotic, or analgesic that will be the focus of the proposed research project.
b. Concept Definition: Clearly describe the concept for feedback regulated drug delivery. Describe the physical mechanisms that will enable regulation based on biomarkers related to toxicity associated with battlefield trauma. Identify which biomarkers will be used for feedback regulation and specify the physiological range required for feedback regulation.
c. Supporting Technical Analysis: Provide a brief analysis of the technical rationale that supports the concept for feedback regulated drug delivery.
d. Research Plan: Provide a brief research plan that describes the methods for achieving the Phase I milestones.
e. Team Expertise and Management Plan: Briefly describe the expertise of the team; include citations to relevant publications. Include a brief management plan for the project.

PHASE I FULL PROPOSAL FORMAT
The general format and content for the Phase I full proposal, including guidelines for the technical and cost volumes, follows the guidelines specified in for the main BAA06-19, which can be found at the website http://www.darpa.mil/baa/baa06-19pt2.html.

The technical section for the Phase I full proposal must include the following elements:

1. A clear definition of the battlefield therapeutic that is being studied and its relevance to tactical field care or battlefield medicine. Any supporting data associated with the effectiveness of the therapeutic in battlefield care should also be included. It is important to note that this program will not support the development or improvement of battlefield therapeutics. Technical concepts related to the development of new or improved drugs for the battlefield will not be considered.
2. The definition of one or more biomarkers that are correlated with the toxic effect of drugs in a battlefield environment. Data that supports the use of these biomarkers as a feedback regulation mechanism must be included in the proposal. The proposal of new or novel biomarkers may also be considered, but a discussion of the relevance of the biomarker to battlefield care must be included in the proposal.
3. The development of a drug delivery system that utilizes biomarkers correlated with toxic effect as a mechanism for feedback regulation.

In addition, the format for the technical volume can be found at the website http://www.darpa.mil/baa/baa06-19.html. The technical section of the full proposal must include
a. Definition of Battlefield Therapeutic: Define a battlefield general anesthetic, local anesthetic, narcotic, or analgesic that will be the focus of the proposed research project.
b. Concept Definition: Clearly describe the concept for feedback regulated drug delivery. Describe the physical mechanisms that will enable regulation based on biomarkers related to toxicity associated with battlefield trauma. Identify which biomarkers will be used for feedback regulation and specify the physiological range required for feedback regulation.
c. Supporting Technical Analysis: Provide a detailed analysis of the technical rationale that supports the concept for feedback regulated drug delivery.
d. Research Plan: Provide a detailed research plan that describes the methods for achieving the milestones specified in this Broad Agency Announcement.
e. Project Milestones and Metrics: Provide several specific, quantitative milestones at intermediate stages of the program to assess progress towards meeting the Phase I milestones discussed above.
f. Phase II Concept: Describe a concept for Phase II development based on successful completion of the Phase I research plan.



WHITE PAPER AND FULL PROPOSAL DEADLINES

White papers will be accepted until October 19, 2006, NO LATER THAN 4:00 PM ET. All white papers will be reviewed no later than November 06, 2006, and recommendations for full proposals will be provided at that time. Full proposals will be due December 14, 2006, NO LATER THAN 4:00 PM 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. The government reserves the right to fund all, some, or no proposals under this BAA addendum.

Evaluation of the proposals will be in accordance with the criteria in BAA06-19, which is found at Part II of the original BAA at http://www.darpa.mil/baa/baa06-19pt2.html. Evaluation factors are listed in decreasing order of importance. For general administrative questions, please refer to the original FEDBIZOPPS solicitation, BAA06-19, of February 8, 2006. http://www.darpa.mil/dso/solicitations/solicit.htm.

Address for Proposal Submission:
DARPA/DSO, ATTN: BAA06-19, Addendum 5
3701 North Fairfax Drive
Arlington, VA 22203-1714

Web address for Proposal Submission: http://www.sainc.com/dso0619/. Those offerors proposing efforts under Grant instruments may alternately submit white papers and full proposals through the Grants.gov website (http://www.grants.gov/).


General Information
In all correspondence, reference BAA06-19, Addendum 5.

Technical Point of Contact

Donald J. Leo, DARPA/DSO; Phone: (571) 218-4939; Email: donald.leo@darpa.mil

Point of Contact

Brett Giroir, Deputy Director, DSO, Phone (571) 218-4224, Fax (571) 218-4553, Email bgiroir@darpa.mil