HR001119S0056.pdf

Broad Agency Announcement ReVector

BIOLOGICAL TECHNOLOGIES OFFICE

HR001119S0056

May 14, 2019

HR001119S0056, ReVector

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. Program Overview

1.2. Technical Approach and Structure

1.3. Program Metrics

1.4. Permits and Compliance

1.5. General Requirements

2. Award Information

2.1. General Award Information

2.2. Fundamental Research

3. Eligibility Information

3.1. Eligible Applicants

3.2. Organizational Conflicts of Interest

3.3. Cost Sharing/Matching

4. Application and Submission Information

4.1. Address to Request Application Package

4.2. Contact and Form of Application Submission

Disclosure of Information and Compliance with Safeguarding Covered Defense Information Controls

4.3. Funding Restrictions

4.4. Other Submission Information

5. Application Review Information

5.1. Evaluation Criteria

5.2. Review of Proposals

6. Award Administration Information

6.1. Selection Notices

6.2. Administrative and National Policy Requirements

6.3. Reporting

6.4. Electronic Systems

7. Agency Contacts

8. Other Information

9. APPENDIX 1 – Volume II checklist

PART I: OVERVIEW INFORMATION

Federal Agency Name – Defense Advanced Research Projects Agency (DARPA), Biological Technologies Office (BTO)

Funding Opportunity Title – ReVector Announcement Type – Initial Announcement Funding Opportunity Number – HR001119S0056 North American Industry Classification System (NAICS) – 541714 Catalog of Federal Domestic Assistance Numbers (CFDA) – 12.910 Research and

Technology Development Dates o Posting Date: May 14, 2019 o Proposal Abstract Due Date and Time: June 4, 2019, 4:00 PM ET o Full Proposal Due Date and Time: July 11, 2019, 4:00 PM ET o BAA Closing Date: July 11, 2019 o Proposers’ Day: May 17, 2019 https://fbo.gov/spg/ODA/DARPA/CMO/DARPA-SN-19-48/listing.html

Concise description of the funding opportunity – The ReVector program aims to develop methods to use human skin microbiomes to modulate chemical production in order to avoid mosquito attraction and feeding and reduce the threat of mosquito-borne disease to Warfighters. Human skin associated microbes interact with metabolites from the body and influence the volatile molecules of each individual, making some individuals more attractive to mosquitoes. This program seeks to develop advanced data analytics and microbiome modulation tools for engineering skin microbiomes and provide new options for the readiness and resiliency of military personnel.

Anticipated individual awards – Multiple awards are anticipated.

Types of instruments that may be awarded – Procurement contract, cooperative agreement, or other transaction.

Agency contact

The BAA Coordinator for this effort may be reached at:

ReVector@darpa.mil

DARPA/BTO

ATTN: HR001119S0056

675 North Randolph Street Arlington, VA 22203-2114 https://fbo.gov/spg/ODA/DARPA/CMO/DARPA-SN-19-48/listing.html mailto:ReVector@darpa.mil

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

The Defense Advanced Research Projects Agency (DARPA) often selects its research efforts through the Broad Agency Announcement (BAA) process. The BAA will appear first on the FedBizOpps website, http://www.fedbizopps.gov/, and the Grants.gov website http://www.grants.gov/. The following information is for those wishing to respond to the BAA.

The Defense Advanced Research Projects Agency (DARPA) is soliciting innovative proposals to develop the ability to use human skin microbiomes to reduce attraction and feeding by mosquitoes or other disease vectors. Proposed research should investigate disruptive approaches to identify microbiome-based metabolites used by mosquitoes to locate humans; design targeted intervention plans to reduce attraction and/or feeding; and develop reliable and safe methods of manipulating the human skin microbiome to achieve desired metabolite production. The integration of these approaches to produce novel microbiome interventions should enable precise, safe and transient products that prevent or significantly reduce incidence of mosquito attraction and feeding to human skin.

1.1. PROGRAM OVERVIEW

Mosquitoes act as a vector for diseases like dengue and malaria that represent a significant danger to the readiness and resiliency of military personnel and more broadly public health.

While multiple approaches to avoiding vector-borne disease exist (e.g., bed nets, repellants or anti-malarial therapeutics), they each have logistical burdens or side effects that make them impractical for use. In addition, these methods of avoiding disease vectors are not feasible during deployment or require frequent reapplication or dosing that can result in inconsistent protection.

Methods of protecting against vector-borne disease that require minimal maintenance, equipment or training and lack deleterious side effects such as odor are required.

Volatiles emitted in human breath attract mosquitoes to the general area of the human. However, it is the heat and volatiles from the skin that direct mosquitoes to the sites on the skin where they feed, ultimately acting as a vector for agents of disease like bacteria, parasites, and viruses. Many volatiles that attract mosquitoes to the skin are produced by the metabolism of organisms in the human skin microbiome. The ReVector program will develop precise, safe, and efficacious technologies to modulate the profile of skin-volatiles by changing the organisms and/or metabolic processes that are present in the skin microbiome in order to reduce attraction and feeding by mosquitoes. It is the proposing team’s responsibility to obtain all necessary federal, state, and local government permits and approvals, and abide by all applicable domestic and international regulations for the proposed work to be conducted. See section 1.4 for additional permitting and compliance requirements.

1.2. TECHNICAL APPROACH AND STRUCTURE

Performers under the ReVector program will develop deployable technologies that use the microbiome to reduce attraction and feeding by at least three genera (i.e., Aedes, Anopheles, and Culex) of disease vectors. For maximum impact, these technologies must be versatile enough to function on multiple representative and distinct microbiomes, to accommodate natural variability http://www.fedbizopps.gov/ http://www.grants.gov/ over time and within a population. Development will require detailed characterization of the human volatilome (the combined volatile molecules given off by the skin) and microbiome to identify the common subset of metabolites, microbes, and pathways that attract mosquitoes searching for a potential blood meal to a human. Teams will need to model and implement safe, effective changes to the microbiome to reduce vector attraction and design interventions to carry out this transformation. This intervention model will need to be resilient and account for varying microbiome and volatile molecule profiles between individual humans.

Modulation of volatile profiles may be designed to actively repel mosquitoes or remove/repress volatiles used by mosquitoes to identify human targets. Mechanisms of engineering the microbiome to conform to a desired volatile profile could include probiotics (addition of beneficial microbes, natural or engineered); prebiotics (changing physiological factors that regulate the composition of the microbiome); precisely targeted antimicrobials to remove microbes; or synthetic biology techniques that change genes/pathways/gene expression of endogenous members of a microbiome. Any proposed mechanism for modifying the skin microbiome should be coupled to safety mechanisms to ensure maximum control and safety. For example, use of antimicrobials should minimize or remove chances of developing antimicrobial resistance, and steps to ensure that engineering endogenous members of the microbiome will also incorporate mechanisms for ensuring that engineered microbes are either transient or mechanisms are in place to remove them. Finally, a means of enabling the transition from the starting microbiome to the desired microbiome will need to be developed and validated. In order to advance the engineering of a human skin microbiome from early proof of concept to clinical translation, development of ReVector technologies will require innovation in several key areas.

New predictive analysis and modeling algorithms will be needed to design microbiome modifications that will perform reliably across scales from metabolite to complex microbial community. Iterative discovery and testing will be required to determine efficacious microbial and metabolic targets and adapt to the dynamic nature of microbial community interactions and test the tools required for modifying the microbiome, and finally, developing or leveraging a system for deploying the modified microbiome onto a human. Performers may initially demonstrate their technologies on in vitro model microbiomes, but in vivo and/or human studies will be required by the completion of the program. Demonstrations of efficacy and safety will facilitate either human or non-human primate trials depending on Food and Drug Administration (FDA)/regulatory requirements by the end of the program.

The intervention and delivery strategy, once applied, should function without requiring additional application for at least two weeks. While the treatment is foreseen to be transient, it should be expected to persist under common hygiene practices (e.g., showering).

1.2.1. Program Structure

ReVector is structured into a four (4) year effort consisting of three (3) phases with Phase I (Base effort) lasting 18 months, Phase II (Option) lasting 18 months, and Phase III (Option) lasting twelve (12) months and two Technical Areas: Technical Area 1 (TA1) – Metabolite Identification and Design; Technical Area 2 (TA2) – Modulate and Deploy. Interdisciplinary teams must address both TAs in parallel to develop a platform technology capable of identifying microbiome leverage points and engineering microbiomes capable of producing a microbiome that reduces attraction and feeding by disease causing vectors.

In Phase I, microbial or metabolic targets must be identified that produce molecules relevant to mosquito attraction and feeding and microbiome alterations will be designed that utilize these leverage points to produce the desired molecules in simplified in vitro communities (18 months).

In Phase II, teams must integrate the tools developed in Phase I to move to animal models and more complex microbiome communities (18 months). Finally, in Phase III teams must perform final demonstrations in human or non-human primate (NHP) studies (12 months). In the case of NHP studies, performers must structure their research plan such that, if successful, they will have sufficiently robust data to justify advancement to human clinical trials by the end of the program.

Total program duration is four (4) years.

TA1: Metabolite Identification and Design TA1 is focused on developing platform technologies for identification of focused leverage points that influence mosquito attraction, specifically defining key metabolic components contributing to a common set of molecules for vector attractant or repellant. Secondly, performers will need to use TA1 technologies to develop a strategy that will use these leverage points for transforming the skin microbiome to reduce mosquito attraction and feeding. The complexity and diversity of the underlying systems creates challenges on several fronts including, but not limited to, olfactory systems of insect vectors, microbial diversity on and between individuals, and complexity of community interactions with respect to metabolism and overall community structure. Teams should generate systematic methods for overcoming these and other challenges to create an enabling technology for designing functional changes to complex microbiomes.

Mosquitoes and other insect vectors have sophisticated olfactory systems composed of hundreds of receptors, presenting a challenge to the identification of biologically active volatiles.

Proposals should define high-throughput methods for determining the volatile compounds that mosquitoes use to identify human targets, and the microbes responsible for producing those compounds. The target space should take human and microbiome metabolism into account, and a set of target volatile compounds and corresponding molecular pathways and/or specific microbes must be identified. Proposals should account for the natural variability in skin microbiome and physiology within populations and over time. If a proposed method focuses on rendering a specific skin microbiome or volatilome unattractive to mosquitos, the proposal must also articulate how the insights from that test case will be generalized, rapidly and practically, to make the intervention transferable to a broader range of use cases. Additionally, if efforts to actively repel mosquitoes will be undertaken, suitable high-throughput methods to identify relevant genes/pathways/molecular products must be clearly articulated.

In parallel with target volatile molecule identification, performers must also develop models to help design effective strategies for microbiome manipulation that account for the complexity of the skin microbiome with regard to community composition, structure, and function. Proposers must develop a predictive modeling platform to design robust interventions for implementation and testing in TA2. Proposals must describe strategies for identifying key leverage points as well as techniques for minimizing the modifications and interventions required to produce a robust solution.

The diversity of individual host metabolism and secretions, as well as diversity of microbiomes on and between individuals, will complicate the design of a “universal” solution. Models must take natural human variability into account and design either a single overall intervention that works on all human skin microbiomes, or if a single intervention is not possible based on human variability, the smallest optimal number of interventions. Proposed technologies should be able to address complex variation including defining skin microbiome types that share molecular properties and corresponding intervention strategies.

Safety is of paramount importance, and models of the impact of the intervention on the microbiome's function should ensure that the modified microbiome achieves the desired molecular profile and has no negative consequences for the Warfighter (e.g., odor, irritation, infection).

The minimum performer objectives for TA1 are as follows:

Deliver a clearly articulated plan for acquiring, processing, and storing data drawn from the research effort, as well as any relevant data from scientific literature.

Deliver models and supporting data that must describe minimal interventions required to modify a microbiome to avoid mosquito attraction and feeding. The model should account for interactions between the host and microbiome, as well as those of individual microbes responsible for phenotypes of interest. The model should detail both the health and safety implications for the individual, as well as the consequences for the metabolite production.

Proposals must outline how the models and supporting data adequately capture natural variability within human metabolism and microbiomes.

TA2: Modulate and Deploy TA2 will focus on development of techniques for precise and safe modification of the skin microbiome based on the TA1 design. When a successful intervention has been validated, the performer must then develop a deployment strategy that can be easily applied by the Warfighter while maintaining function for at least two weeks.

The proposal should describe computational and molecular technology required to facilitate microbiome modification. Methods of modification can incorporate (but are not limited to):

Addition of microbes that possess a preferred phenotype such as probiotics.

Removal of microbes through targeted means such as phages, antibiotics, CRISPR Cas9 etc.

Prebiotics could be used to control conditions and select for desirable organisms/metabolic pathways or select against undesirable organisms/metabolic pathways.

Synthetic biology could be used to modify genes or pathways in endogenous or engineered microbes. In this case, appropriate safety mechanisms for controlling transience or removal of the engineered organism should be addressed.

Many endogenous members of the human skin microbiome perform beneficial/commensal activities and proposals should articulate methods ensuring beneficial phenotypes will not be lost during microbiome modification. In addition, immunology studies of the proposed treatment’s effects should be detailed to ensure that treatment does not result in a deleterious immune response.

Deployment of the final microbiome strategy onto the skin will be the final component of the ReVector platform. The following objectives must be addressed:

Treatment should be technically simple to apply, without significant burden on the Warfighter—oral or manual delivery of interventions, for example, will be significantly preferred over delivery via intravenous injection or full-body-immersion.

The treatment should be stable within 48 hours and persistent for at least 2 weeks given reasonable hygiene practices (e.g., showering and washing with non-antibiotic soap).

FDA-approved as safe or ready for investigational new drug application (IND) and human clinical trials by the end of the program. All formulations (including those that qualify as Generally Recognized As Safe) will be required to work with the FDA to ensure both safety and efficacy are demonstrated to facilitate human trials. Proposed biotherapeutics that do not meet FDA requirements for human use will be considered unresponsive. Additional information about the FDA approval process for biotherapeutics can be found at: https://www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf

Integration TA1 and TA2 described above must be integrated into a single system capable of modifying a human’s microbiome metabolite production. All proposing teams must address both TAs to ensure a complete, integrated system by the end of the program. Initial integration of the design and modifications required should be complete by the end of Phase I, while deployment strategy will be required for completion of Phase II. Each of the TAs will remain active for all three phases as it is anticipated that iterative improvement and optimization will be required throughout the project.

Independent Validation and Verification Engineered microbiomes will be tested by third parties at the end of each phase to validate performance and accelerate the development and approval process. Independent labs from Department of Defense (DoD) or U.S. Government agencies will validate the ability of the engineered communities to successfully evade mosquitoes at the end of each Phase. If a microbiome expert is required to maintain the samples being tested by the independent verification and validation (IV&V) team, the proposers should account for tasks and costs associated with sending a team member to participate in IV&V activities in both the Statement of Work (SOW) and budget.

https://www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf

1.3. PROGRAM METRICS

In order for the Government to evaluate the effectiveness of a proposed solution in achieving the stated program objectives, proposers should note that the Government hereby promulgates the following program metrics that may serve as the basis for determining whether satisfactory progress is being made to warrant continued funding of the program. Although the following program metrics are specified, proposers should note that the Government has identified these goals with the intention of bounding the scope of effort, while affording the maximum flexibility, creativity, and innovation in proposing solutions to the stated problem. Proposers are expected to define additional quantitative and qualitative success criteria as needed. Proposers must clearly and uniquely itemize tasks needed to accomplish planned milestones and deliverables.

Proposals should cite the quantitative and qualitative success criteria that the proposed effort will achieve by the time of each phase’s program metric measurement.

Proposals must be written to address milestones in both TAs: Identify and Design (TA1) and Modulate and Deploy (TA2). Proposals that do not address both technical areas will be considered non-conforming and rejected without review. The milestones and metrics for each technical area and phase are outlined below. Proposers must explain quantitative success criteria for each milestone, and information on how it will be achieved, in their SOW.

Phase I (Base) (months 1 through 18): In vitro experiments using model systems

Technical Area 1: Identify and Design

Goal: Identify microbiome constituents and cognate metabolites which contribute to production of volatiles that are detectable by mosquitoes, or design a method for microbial production of a molecule or molecules capable of repelling disease vectors. Once specific targets are identified, performers will design an intervention that targets the most influential leverage points with the modifications needed to reproduce a microbiome that will reduce mosquito attraction to an in vitro model microbial community. The predicted interventions designed in this TA will be evaluated in TA2.

Milestones:

(i) Identify key microbiome elements responsible for mosquito attraction or genes/pathways capable of repelling mosquitoes (6 months).

(ii) Develop multiple in vitro model microbiomes for evaluation of interventions. (12 months)

(iii) Generate a blueprint of modifications that would disrupt mosquito-attraction by removing/reducing metabolite and/or volatile production or generating a means of actively repelling mosquitoes (12 months).

Note: Final Phase I demonstration is associated with TA2 (18 months).

Metrics:

(i) Identify ≥ 5 molecules associated with mosquito attraction and feeding, and associate them with their microbiome sources; alternatively, identify viable pathways for production of ≥ 5 candidate molecules that actively repel mosquitoes (6 months).

(ii) Establish ≥ 5 distinct in vitro model microbial communities, based on human microbiomes that reflect natural variability within a population or over time, that either produce volatiles associated with mosquito attraction and feeding or produce molecules that repel mosquitoes (9 months).

Technical Area 2: Modulate and Deploy

Goal: In Phase I, the TA2 objective is to enable the modification of in vitro microbiomes to demonstrate the feasibility of controlling their volatile outputs or producing a repellant.

The reconfiguration of microbial communities can be mediated through a combination of biological, environmental, and genetic perturbations. The initial integration of the design and the modifications required should be complete by the end of Phase I. This integration will lead to insight into appropriate microbiome compositions that have the potential to reduce mosquito attraction and feeding.

Milestones:

(i) Develop tools to modify in vitro model microbiome function and/or composition to either reduce production of volatiles that attract mosquitoes or repel mosquitoes in one in vitro model microbiome (12 months).

(ii) Extend demonstration of these tools to at least five model microbiomes (18 months).

Metrics:

(i) Achieve ≥ 5-fold reduction of molecules associated with mosquito attraction, and/or achieve ≥ 5-fold increase in repellant molecules; interventions should be demonstrated on a single in vitro microbiome (12 months).

(ii) Achieve a ≥ 5-fold modification of attractant/repellant volatiles from ≥ 5 in vitro microbiomes (18 months). Successful demonstration of this modification and confirmation via IV&V is necessary for advancement to Phase II.

IV&V:

At month 18, performers must demonstrate an intervention that leads to ≥ 5-fold reduction in mosquito attraction and feeding for in vitro model communities that the performers will provide to the IV&V team.

Phase II (Option) (months 18 through 36): Pre-clinical animal studies validating safety and efficacy.

Technical Area 1: Identify and Design

Goal: Establish and characterize modified animal model microbiomes, and continue the design-build-test cycle with TA2 as successive microbiome changes are made. Proposers must provide detailed justifications for the animal models that will be used. Once initial microbiome modifications have been tested in Phase I, performers will design improved interventions that incorporate this understanding of the most influential leverage points in order to further improve the efficacy of the modified microbiome.

Milestones:

Establish representative human microbiomes on relevant animal models and confirm the efficacy of mosquito attractant or repellant compounds depending on the approach taken (24 months).

Metrics:

(i) Demonstrate relevant data (genome sequencing or otherwise) confirming establishment of ≥ 5 distinct model human microbiomes on relevant animal models (24 months).

(ii) Demonstrate volatilome or empirical mosquito attraction data confirming that applied microbiomes reduce the quantity of volatile compounds associated with mosquito attraction produced by the skin microbiome of animal models. Alternatively, demonstrate that pathways for production of mosquito repelling molecules have been added to the skin microbiomes of the animal models (24 months).

Note: Final Phase II demonstration is associated with TA2 (36 months).

Technical Area 2: Modulate and Deploy

Goal: Develop multiple unique human microbiome models on animals and demonstrate a safe and efficacious intervention that is capable of reducing mosquito attraction and feeding. When a successful intervention has been validated, the performer will then develop a deployment strategy that has a low logistical burden on the Warfighter. Both the deployment strategy and the intervention will require validation as safe per FDA standards. The modifications should be stable within two (2) days and persist for at least two (2) weeks. In order to continue towards development for human use in Phase III, initial filings to approve human studies must be submitted by the end of Phase II.

Milestones:

(i) Modify the skin microbiome of a single animal model hosting a human microbiome, to reduce mosquito attraction and feeding (30 months).

(ii) Modify microbiome in animal models hosting 10 distinct human microbiomes to reduce mosquito attraction and feeding (36 months).

(iii) Validate that the microbiome-altering intervention and molecular alterations are safe according to FDA standards in the appropriate animal model for pre-clinical testing; initial filings for human studies must be submitted to continue to Phase III (36 months).

Metrics:

(i) Achieve ≥ 10-fold reduction of molecules associated with mosquito attraction, and/or achieve ≥ 10-fold increase in repellant molecules (30 months).

(ii) Achieve a ≥ 10-fold modification of relevant attractant/repellant compounds associated with mosquito attraction in 10 distinct human microbial communities hosted on animal models (36 months).

IV&V:

At month 36, performers must demonstrate an intervention that leads to ≥ 10-fold reduction in mosquito attraction and feeding for ≥ 10 distinct model communities provided to the IV&V team, on relevant animal models.

Phase III (Option) (months 36 through 48): Human or non-human primate trials and IV&V

Goal: Using an intervention based on the work in Phases 1 and 2, modify the innate human or non-human primate microbiome and demonstrate successful reduction of subjects to attraction and feeding by mosquitoes. In the instance of non-human primate studies, the final goal will be to have achieved optimal intervention performance and gained approval to progress to human clinical trials by the end of the program.

Milestones:

Demonstrate efficacy of a system for reducing mosquito attraction and feeding in humans or non-human primate model (48 months).

Metrics:

Upon treatment with microbiome intervention achieve a 100-fold reduction in mosquito attraction and feeding in 10 distinct human or non-human primates (48 months).

IV&V:

At month 48, the IV&V team will use the intervention developed by performer teams and demonstrate that it leads to ≥ 100-fold reduction in mosquito attraction and feeding for 10 distinct human or non-human primate subjects.

1.4. PERMITS AND COMPLIANCE

It is the proposing team’s responsibility to obtain all necessary federal, state, and local government permits and approvals and abide by all applicable laws where necessary for the proposed work to be conducted. All international laws must also be followed.

Proposing teams must design proposals so that they minimize any adverse effects on humans.

Proposals must include sufficient documentation to demonstrate that all federal laws and regulations including FDA requirements for human clinical trials will be followed. If the proposal will use Generally Recognized as Safe (GRAS) organisms that do not require FDA approval, sufficient documentation of the GRAS status of the organisms proposed must be included. Please reference FDA 80 FR 17050, “Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information” for further guidance on the FDA regulatory process for live biotherapeutics:

https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor mation/Guidances/General/UCM292704.pdf.

Failure to apply for and/or obtain federal, state and local permits, approvals, letters of agreement or failure to provide a path towards regulatory approval where necessary will delay award of funds if a project is selected for funding.

Proposing teams must design proposals so that they minimize any adverse effects on the environment. Proposals must have sufficient documentation to show the proposal is categorically excluded from further National Environmental Policy Act (NEPA) analysis or whether an Environmental Assessment or Environmental Impact Statement (EIS) will be necessary for the proposed work. Failure to apply for and/or obtain federal, state, and local permits, approvals, letters of agreement or failure to provide environmental analysis where necessary (e.g., NEPA, EIS) will delay award of funds if a project is selected for funding. See Sections 4.2.1(D)(11) and 4.2.2(a)-Section IIB for additional detail on required documentations.

DARPA does not consider the use of biological agents to be in the scope of this BAA, and all proposals shall discuss how the proposed technical approach is not a contravention of the Biological Weapons Convention. See https://www.state.gov/t/isn/bw/c48738.htm.

1.5. GENERAL REQUIREMENTS

In addition to the requirements above, proposers to the ReVector program must address each of the following:

1.5.1. Teaming

Proposers are responsible for assembling a complete team that has technical expertise, capabilities, and facilities to address all requirements of the program. Proposers must address both technical areas, which should run in parallel. A complete proposer team should therefore not only have the ability to meet the technical challenges of each TA and create an integrated platform for modeling and engineering human skin microbiome but also perform relevant experiments with animal models at appropriate biosafety level (BSL)/containment levels. It is also essential that proposer teams include members that have industrial and commercial experience to aid in focusing technology research and development strategy for eventual clinical translation. This could include, for example, expertise in medical product development or microbiome intervention (e.g., probiotics) for use in preclinical and clinical settings to effectively navigate the preparatory process for IND/Emergency Use Authorization (EUA), or equivalent, submission during the program effort. Proposers must describe any formal teaming agreements that are required to execute this program. All teams are encouraged to identify a Project Manager to serve as the primary point of contact to communicate with the DARPA Program Manager and Contracting Officer Representative, coordinate effort across performer teams, organize regular performer meetings or discussions, facilitate data sharing, and ensure timely completion of milestones and deliverables. For teams that are not physically co-located, proposers must articulate how logistical challenges will be overcome to ensure smooth collaboration and an integrated work product.

https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/UCM292704.pdf https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/UCM292704.pdf https://www.state.gov/t/isn/bw/c48738.htm

1.5.2. Controlled Unclassified Information (CUI)

To prevent the release of sensitive technical information, certain aspects of the proposed research may be considered CUI if they reveal host susceptibilities to threats or other vulnerabilities, and may require safeguarding or dissemination controls, pursuant to and consistent with applicable law, regulations, and government-wide policies. Proposals that anticipate the production of any such information must deliver a detailed risk mitigation plan to DARPA (see Section 4.2.2.

Proposal Format Section II: I). Performers must partition potentially sensitive tasks from non-sensitive research efforts. All performers (prime contractor and subcontractor) desiring public release of project information that may contain CUI as defined above must submit a request for public release from DARPA/PRC in accordance with their contractual requirements.

1.5.3. Ethical, Legal, and Societal Implications (ELSI)

DARPA maintains its commitment to ensuring that efforts funded under this BAA adhere to ethical and legal regulations currently in place for Federal and DoD-funded research. Program developments will be discussed with a panel of expert external advisors with expertise in bioethical issues that may emerge as a consequence of advances in biomedical science and technology, including human microbiome engineering. Proposers to this BAA should address potential ethical, legal, and societal implications of the proposed technology, with a special emphasis on strategies to enable safe, transient, non-permanent human skin microbiome engineering.

1.5.4. Regulatory Strategy

Proposers must present a detailed plan for early and continued engagement with regulators (e.g., FDA, Environmental Protection Agency) throughout the program to discuss developing technologies and challenges in order to inform and improve the design of microbiome intervention strategies during the program, and to facilitate the eventual translation of the technology to field deployment. Ideally, proposers will identify the applicant for the Live Biotherapeutic IND submission at the time of proposal submission.

1.5.5. Transition Strategy

Proposers must present a detailed plan for transition of the technologies developed under the program for human testing and product formulation. It is anticipated that the ReVector microbiome engineering platform will be suitable for advanced development and licensing for many high impact applications in global health and pharmaceutical development. It is critical that ReVector platform technologies be developed in a manner that positions them for further development and deployment by the end of the program.

1.5.6. Deliverables

All products, material and otherwise, that will be provided to the Government as outcomes from conducted research should be defined as part of the proposal. Performers need to reserve time and budget to fulfill obligations for travel to review meetings and the transmission of report documentation.

End of Phase reports: At the end of Phase 1 and Phase II, prior to the initiation of the subsequent phase, performers must draft and present to DARPA a written report of all research activities and metrics satisfied. This report should contain as much supporting data as can be reasonably conveyed.

Predictive analysis and modeling algorithms Monthly financial reports: Performers are required to provide financial status updates.

These reports should be in the form of an editable MS Excel file, and should provide financial data including, but not limited to, the following: program spend plan by phase and task, incurred program expenditures to date by phase and task, and invoiced program expenditures to date by phase and task. The prime Performer is to include information for itself and all subawardees/subcontractors.

Monthly technical progress reports: Each month (or as close to as scheduling permits), performers are required to provide research updates. These reports should be in the form of a standardized slide presentation given to DARPA and discussed with the program management team via teleconference. Length and detail level should be at the discretion of the Program Manager.

Quarterly technical reports: The reports shall be prepared and submitted in accordance with the procedures contained in the award document.

Semi-Annual Reviews: Leadership from each performer team (with additional key personnel at the discretion of the Principal Investigator (PI)) will be required to present research progress in person, twice annually. The purpose of these reviews is to ensure adequate engagement with the DARPA team to discuss details that might otherwise fall outside the scope of a routine technical brief, and provide opportunities to discuss progress towards milestones and scientific goals, any ongoing technical or programmatic challenges that must be overcome to achieve the overarching goals of the program.

Final Program Report: When the final funding phase closes out, performer teams will provide a final report that summarizes all research activities, outcomes, and molecular mechanisms discovered during the program.

Any publications, research presentations, patent applications that result from the research pursued as part of the ReVector program.

Any additional deliverables requested by the Contracting agent for this program.

2. Award Information

2.1. GENERAL AWARD INFORMATION

Multiple awards are possible. The amount of resources made available under this BAA will depend on the quality of the proposals received and the availability of funds.

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this solicitation and to make awards without discussions with proposers. The Government also reserves the right to conduct discussions if it is later determined to be necessary. If warranted, portions of resulting awards may be segregated into pre-priced options. Additionally, DARPA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event that DARPA desires to award only portions of a proposal, negotiations may be opened with that proposer. The Government reserves the right to fund proposals in phases with options for continued work, as applicable.

The Government reserves the right to request any additional, necessary documentation once it makes the award instrument determination. Such additional information may include but is not limited to Representations and Certifications (see Section VI.B.2., “Representations and Certifications”). The Government reserves the right to remove proposers from award consideration should the parties fail to reach agreement on award terms, conditions, and/or cost/price within a reasonable time, and the proposer fails to timely provide requested additional information. Proposals identified for negotiation may result in a procurement contract, cooperative agreement, or other transaction, depending upon the nature of the work proposed, the required degree of interaction between parties, whether or not the research is classified as Fundamental Research, and other factors.

Proposers looking for innovative, commercial-like contractual arrangements are encouraged to consider requesting Other Transactions. To understand the flexibility and options associated with Other Transactions, consult http://www.darpa.mil/work-with-us/contract-management#OtherTransactions.

In accordance with 10 U.S.C. § 2371b(f), the Government may award a follow-on production contract or Other Transaction (OT) for any OT awarded under this BAA if: (1) that participant in the OT, or a recognized successor in interest to the OT, successfully completed the entire prototype project provided for in the OT, as modified; and (2) the OT provides for the award of a follow-on production contract or OT to the participant, or a recognized successor in interest to the OT.

In all cases, the Government contracting officer shall have sole discretion to select award instrument type, regardless of instrument type proposed, and to negotiate all instrument terms and conditions with selectees. DARPA will apply publication or other restrictions, as necessary, if it determines that the research resulting from the proposed effort will present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Any award resulting from such a determination will include a requirement for DARPA permission before publishing any information or results on the program. For more information on publication restrictions, see the section below on Fundamental Research.

2.2. FUNDAMENTAL RESEARCH

It is DoD policy that the publication of products of fundamental research will remain unrestricted to the maximum extent possible. National Security Decision Directive (NSDD) 189 defines fundamental research as follows:

‘Fundamental research’ means basic and applied research in science and engineering, the results of which ordinarily are published and shared broadly within the scientific community, as distinguished from proprietary research and from industrial development, http://www.darpa.mil/work-with-us/contract-management#OtherTransactions http://www.darpa.mil/work-with-us/contract-management#OtherTransactions design, production, and product utilization, the results of which ordinarily are restricted for proprietary or national security reasons.

As of the date of publication of this BAA, the Government expects that program goals as described herein either cannot be met by proposers intending to perform fundamental research or the proposed research is anticipated to present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Therefore, the Government anticipates restrictions on the resultant research that will require the awardee to seek DARPA permission before publishing any information or results relative to the program.

Proposers should indicate in their proposal whether they believe the scope of the research included in their proposal is fundamental or not. While proposers should clearly explain the intended results of their research, the Government shall have sole discretion to determine whether the proposed research shall be considered fundamental and to select the award instrument type. Appropriate language will be included in resultant awards for non-fundamental research to prescribe publication requirements and other restrictions, as appropriate. This language can be found at http://www.darpa.mil/work-with-us/additional-baa.

For certain research projects, it may be possible that although the research to be performed by a potential awardee is non-fundamental research, its proposed subawardee’s effort may be fundamental research. It is also possible that the research performed by a potential awardee is fundamental research while its proposed subawardee’s effort may be non-fundamental research.

In all cases, it is the potential awardee’s responsibility to explain in its proposal which proposed efforts are fundamental research and why the proposed efforts should be considered fundamental research.

3. Eligibility Information

3.1. ELIGIBLE APPLICANTS

All responsible sources capable of satisfying the Government’s needs may submit a proposal that shall be considered by DARPA.

3.1.1. Federally Funded Research and Development Centers (FFRDCs) and Government Entities

FFRDCs FFRDCs are subject to applicable direct competition limitations and cannot propose to this BAA in any capacity unless they meet the following conditions: (1) FFRDCs must clearly demonstrate that the proposed work is not otherwise available from the private sector. (2) FFRDCs must provide a letter on official letterhead from their sponsoring organization citing the specific authority establishing their eligibility to propose to Government solicitations and compete with industry, and their compliance with the associated FFRDC sponsor agreement’s terms and conditions. This information is required for FFRDCs proposing to be awardees or subawardees.

http://www.darpa.mil/work-with-us/additional-baa

Government Entities Government Entities (e.g., Government/National laboratories, military educational institutions, etc.) are subject to applicable direct competition limitations. Government entities must clearly demonstrate that the work is not otherwise available from the private sector and provide written documentation citing the specific statutory authority and contractual authority, if relevant, establishing their ability to propose to Government solicitations. This information is required for Government Entities proposing to be awardees or subawardees.

Authority and Eligibility At the present time, DARPA does not consider 15 U.S.C. § 3710a to be sufficient legal authority to show eligibility. While 10 U.S.C.§ 2539b may be the appropriate statutory starting point for some entities, specific supporting regulatory guidance, together with evidence of agency approval, will still be required to fully establish eligibility. DARPA will consider FFRDC and Government entity eligibility submissions on a case-by-case basis; however, the burden to prove eligibility for all team members rests solely with the proposer.

3.1.2. Non-U.S. Organizations

Non-U.S. organizations and/or individuals may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances.

3.2. ORGANIZATIONAL CONFLICTS OF INTEREST

FAR 9.5 Requirements In accordance with FAR 9.5, proposers are required to identify and disclose all facts relevant to potential OCIs involving the proposer’s organization and any proposed team member (subawardee, consultant). Under this Section, the proposer is responsible for providing this disclosure with each proposal submitted to the BAA. The disclosure must include the proposer’s, and as applicable, proposed team member’s OCI mitigation plan. The OCI mitigation plan must include a description of the actions the proposer has taken, or intends to take, to prevent the existence of conflicting roles that might bias the proposer’s judgment and to prevent the proposer from having unfair competitive advantage. The OCI mitigation plan will specifically discuss the disclosed OCI in the context of each of the OCI limitations outlined in FAR 9.505-1 through FAR 9.505-4.

Agency Supplemental OCI Policy In addition, DARPA has a supplemental OCI policy that prohibits contractors/performers from concurrently providing Scientific Engineering Technical Assistance (SETA), Advisory and Assistance Services (A&AS) or similar support services and being a technical performer.

Therefore, as part of the FAR 9.5 disclosure requirement above, a proposer must affirm whether the proposer or any proposed team member (subawardee, consultant) is providing SETA, A&AS, or similar support to any DARPA office(s) under: (a) a current award or subaward; or (b) a past award or subaward that ended within one calendar year prior to the proposal’s submission date.

If SETA, A&AS, or similar support is being or was provided to any DARPA office(s), the proposal must include:

The name of the DARPA office receiving the support;

The prime contract number;

Identification of proposed team member (subawardee, consultant) providing the support; and An OCI mitigation plan in accordance with FAR 9.5.

Government Procedures In accordance with FAR 9.503, 9.504 and 9.506, the Government will evaluate OCI mitigation plans to avoid, neutralize or mitigate potential OCI issues before award and to determine whether it is in the Government’s interest to grant a waiver. The Government will only evaluate OCI mitigation plans for proposals that are determined selectable under the BAA evaluation criteria and funding availability.

The Government may require proposers to provide additional information to assist the Government in evaluating the proposer’s OCI mitigation plan.

If the Government determines that a proposer failed to fully disclose an OCI; or failed to provide the affirmation of DARPA support as described above; or failed to reasonably provide additional information requested by the Government to assist in evaluating the proposer’s OCI mitigation plan, the Government may reject the proposal and withdraw it from consideration for award.

3.3. COST SHARING/MATCHING

Cost sharing is not required; however, it will be carefully considered where there is an applicable statutory condition relating to the selected funding instrument. Cost sharing is encouraged where there is a reasonable probability of a potential commercial application related to the proposed research and development effort.

4. Application and Submission Information

4.1. ADDRESS TO REQUEST APPLICATION PACKAGE

This announcement, any attachments, and any references to external websites herein constitute the total solicitation.