BARDA CBRN BAA- 11-100-SOL-00009.pdf

BARDA CBRN BAA- 11-100-SOL-00009

Overview Information

Agency Name: Department of Health and Human Services, Office of the Secretary, Assistant

Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority 330 Independence Avenue, SW, Rm G640, Washington, DC, 20201

Issuing Office: Department of Health and Human Services, Office of the Secretary, Assistant

Secretary for Preparedness and Response, Acquisition Management, Contracts & Grants, 330 Independence Avenue, SW, Rm G640, Washington, DC, 20201

Research Opportunity Title: BARDA Broad Agency Announcement for the Advanced

Research and Development of Chemical, Biological, Radiological, and Nuclear Medical Countermeasures

Announcement Type and Date: Initial Announcement, March 4, 2009. Renewal Announcement March 4, 2011

Eligible Applicants: This BAA is open to ALL responsible sources. Offerors may include single entities or teams from private sector organizations, Government laboratories, Federally Funded Research and Development Centers (FFRDCs), and academic institutions.

Federally Funded Research and Development Centers (FFRDCs), are eligible to respond to this BAA, individually or as a team member of an eligible principal Offeror, as so long as they are permitted under the sponsoring agreement between the Government and the specific FFRDC.

To be eligible for award, a prospective recipient must meet certain minimum standards pertaining to financial resources, ability to comply with the performance schedule, prior record of performance, integrity, organization, experience, operational controls, technical controls, technical skills, facilities, and equipment.

Historically Black Colleges and Universities (HBCU), Minority Institutions (MI), Small Business concerns, Small Disadvantaged Business concerns, Women-Owned Small Business concerns, Veteran-Owned Small Business concerns, Service-Disabled Veteran-Owned Small Business concerns, and HUB Zone Small Business concerns are encouraged to submit proposals and to join other entities as team members in submitting proposals.

Research Opportunity Description: The Biomedical Advanced Research and Development Authority solicits the advanced research and development of medical countermeasures for chemical, biological, radiological, and nuclear agents that threaten the U.S. civilian population.

BARDA anticipates that research and development activities awarded under this BAA will serve to advance candidate medical countermeasures towards FDA licensure/approval and consideration for acquisition.

TABLE OF CONTENTS

Overview Information

TABLE OF CONTENTS

Pre-Proposal Conferences:

Part I: Research Areas of Interest

Area of Interest #1: Vaccines Area of Interest #2: Antitoxins and Therapeutics Area of Interest #3: Antimicrobial Drugs Area of Interest #4: Radiological/Nuclear Threat Medical Countermeasures . 10 Area of Interest #5: Chemical Threat Medical Countermeasures:

Area of Interest #6: Clinical Diagnostics Tools:

Part II: Research and Technical Objectives Part III: Reporting Requirements and Deliverables Part IV: Proposal Preparation and Submission

Section 1: The Application Process Section 2: Stage 1 Quad Chart and White Paper Preparation Section 3: Quad Chart and White Paper Submission Section 4: Stage 2 Full Proposal Preparation Section 5: Full Proposal Submission Section 6: General Information

Part V: Proposal Evaluation Part VI: Special Instructions Part VII: Attachments

Attachment 1: Technology Readiness Level (TRL) Definitions for Medical In-Vitro Diagnostic Devices……………………………………………………………… ... 36 Attachment 2: Volume II - Breakdown Of Proposed Estimated Cost (Plus Fee) And Labor Hours Attachment 3: Security Template Attachment 4: Summary of Related Activities Attachment 5: Government Notice for Handling Proposals Attachment 6: Quad Chart and White Paper Format Template Attachment 7: Target Product Profile Template Attachment 8: Additional Requirement Information…………………………… 56

BARDA CBRN BAA- 11-100-SOL-00009

INTRODUCTION

This Broad Agency Announcement (BAA), which sets forth research areas of interest for the Biomedical Advanced Research and Development Authority (BARDA), is issued under paragraph 6.102(d)(2) of the Federal Acquisition Regulation (FAR). Proposals selected for award are considered to be the result of full and open competition and in full compliance with the provision of Public Law 98-369, "The Competition in Contracting Act of 1984" and subsequent amendments.

BARDA, the lead agency for acquisition of medical countermeasures (MCM) within the Office of the Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services (HHS) is soliciting proposals for the advanced research and development of MCM for chemical, biological, radiological, and nuclear (CBRN) agents that threaten the U.S.

civilian population. The continuing threat of terrorism underscores the compelling need to develop new and improved MCM for protecting all segments of the civilian population. This BAA will support the development of candidate products and diagnostic tools to meet the challenging lifecycle requirements of CBRN MCM (e.g. post-exposure efficacy, extended shelf life, storage, distribution, and dispensing).

BARDA‟s priorities are aligned with the preparedness mission of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), as articulated in the PHEMCE

Implementation Plan (http://www.hhs.gov/aspr/barda/phemce/index.html).

Specifically, HHS has generally adopted a strategy of developing and acquiring medical countermeasures for post-event response to CBRN threats. Preventive measures are appropriate only for threats of such potential catastrophic consequence that a pre-event strategy will be examined in order to reduce vulnerability and mitigate post-event consequences.

Therapeutics and diagnostics or the use of post-event prophylaxis will be the preferred strategy for all other threats. Priority will be placed on medical countermeasures that focus on post-event prophylaxis or post-exposure treatment. To that end, BARDA supports the advanced research/development and acquisition of MCM such as vaccines, therapeutics, and diagnostics.

For additional requirements information, please refer to Attachment 8

The Pandemic and All Hazard Preparedness Act (PAHPA;

http://www.hhs.gov/aspr/opsp/pahpa/index.html) directs BARDA to promote (i) innovations in technologies that may assist MCM advanced research and development, (ii) research and development of tools, devices, and technologies, and (iii) research to promote strategic initiatives, such as rapid diagnostics, broad spectrum antimicrobials, and vaccine manufacturing technologies.

The BAA is open to all responsible sources. Offerors may include single entities or teams from private sector organizations, Government laboratories, Federally Funded Research and Development Centers (FFRDCs), and academic institutions.

Federally Funded Research and Development Centers (FFRDCs) are eligible to respond to this BAA, individually or as a team member of an eligible principal Offeror, as long as they are permitted under the sponsoring agreement between the Government and the specific FFRDC.

To be eligible for award, a prospective recipient must meet certain minimum standards pertaining to financial resources, ability to comply with the performance schedule, prior record of http://www.hhs.gov/aspr/barda/phemce/index.html http://www.hhs.gov/aspr/opsp/pahpa/index.html performance, integrity, organization, experience, operational controls, technical controls, technical skills, facilities, and equipment.

Historically Black Colleges and Universities (HBCU), Minority Institutions (MI), Small Business concerns, Small Disadvantaged Business concerns, Women-Owned Small Business concerns, Veteran-Owned Small Business concerns, Service-Disabled Veteran-Owned Small Business concerns, and HUB Zone Small Business concerns are encouraged to submit proposals and to join other entities as team members in submitting proposals.

The purpose of this BAA is to solicit proposals that focus on one or more of the following solicited areas of interest as listed here and further described in Part I of this announcement.

Research Areas of Interest:

Vaccines

Antitoxins and Therapeutics

Antimicrobial Drugs

Radiological and Nuclear Threat Countermeasures

Chemical Threat Countermeasures

Diagnostics

Research and technical objectives are described in Part II and efforts proposed by Offerors may include activities in Non-Clinical Research and Development, Process Development, Formulation, and Manufacturing Development, and Clinical Evaluation. For drug and biologic medical countermeasure development efforts, Offerors shall propose a Statement Of Work (SOW) preferred to be consistent with activities between Integrated Technology Readiness Levels (TRLs) 6 to 7 (see https://www.medicalcountermeasures.gov/Integrated_TRLs.aspx). For Diagnostic, Offerors shall propose a SOW consistent with activities at TRLs 4 or greater (refer to TRLs in Attachment 1). For CRN (Research Areas 4 and 5), Offerors shall propose a SOW that is consistent with activities occurring at TRL 3 or greater (see Attachment 1). Please note that all activities within a TRL level (or sublevel) must be completed to have achieved that TRL status.

The BAA will be conducted in two stages:

In Stage 1, Offerors shall submit a Quad Chart and White Paper summarizing the proposed project. All Quad Charts and White Papers must be prepared in accordance with the instructions contained in Part IV, and may be submitted at any time during the BAA. Brochures or other descriptions of general organizational or individual capabilities will not be accepted.

Acknowledgement of receipt (electronic) will be made within one week. For areas 1, 2, 3, and 6 there are four submission deadlines: Dec. 1, March 1, June 1 and September 1. Areas 4 and 5 submissions will remain open for continuous submissions. Decision letters to Offerors will be sent within 90 calendar days of submission or within 90 calendar days after the submission deadline.

In Stage 2, Offerors receiving a favorable evaluation will be asked to prepare a Full Proposal and submit to BARDA within 75 calendar days depending on time and funding constraints.

Instructions for completing the Full Proposal are found in Part IV of this announcement. A request to submit a Full Proposal does not assure an award. There are no specified funding limitations identified for proposals submitted under this BAA. The budget shall be commensurate with the nature and complexity of the proposed research. The Government intends to make an award decision within 180 days after submission of Full Proposals.

https://www.medicalcountermeasures.gov/Integrated_TRLs.aspx

Offerors contemplating submitting Quad Charts, White Papers, and Full Proposals are strongly encouraged to contact the appropriate technical Point of Contact (POC) at BARDA (see names and e-mail addresses listed immediately after each research area of interest). Offerors are advised that only a Contracting Officer may obligate the Government to any agreement involving expenditure of Government funds. Once a white paper or full proposal has been submitted, all communications must be through the BARDA Contracting Office (The Office of Acquisitions Management, Contracts & Grants).

The costs of preparing responses to this BAA are not considered an allowable direct charge on any resultant award.

Quad Chart and White Papers and / or Full Proposals WILL NOT BE ACCEPTED after 4:30 PM (Eastern Standard Time) on 3 March 2012.

In accordance with federal statutes, regulations, and HHS policies, no person on grounds of race, color, age, sex, national origin, or disability shall be excluded from participation in, be denied the benefits of, or be subjected to discrimination under any program or activity receiving financial assistance from the HHS.

ASPR reserves the right to fund all, some, or none of the proposals submitted. While award is anticipated to occur according to the stated schedule, Offerors that are not responsive to BARDA requests for information in a timely manner, defined as meeting government deadlines established and communicated with the request, may be removed from award consideration.

ASPR reserves the right to award the instrument best suited to the nature of the research proposed and may award any appropriate contract type under the Federal Acquisition Regulation. BARDA may also elect to make awards in the form of grants and cooperative agreements, with the possibility of awarding Other Transactions (OT) agreements in the future as appropriate.

Multiple awards of various values are anticipated and are dependent upon the proposals‟ scientific and technical merits, how well the proposals fit BARDA‟s areas of interest, and available funding.

Special instructions will be advertised via the BAA as they become apparent. These additional instructions are tailored to a specific area of interest and may have a unique submittal date. The information requested in these instructions should be used along with Part IV of the BAA to format and prepare the Technical and Business Proposals.

Offerors should follow the instructions in Part IV of the BAA, and include the information requested therein. Please see Part VI for updated Special Instructions associated with this renewal.

Anticipated funding for the program (not per contract or award) may range from $5M to $750M dollars subject to congressional appropriations. This funding profile is an estimate only and will not be a contractual obligation for funding. All funding is subject to change due to government discretion and availability.

All administrative inquires regarding this BAA shall be addressed to CBRN-BAA-11@hhs.gov.

Technical questions shall be referred to the Point Of Contacts (POCs) shown following each mailto:CBRN-BAA-11@hhs.gov research area of interest. When an inquiry is made, please include all pertinent contact information.

This BAA is available on the following websites:

https://www.fbo.gov https://www.medicalcountermeasures.gov/ http://www.phe.gov/

This BAA is a continuously open announcement valid throughout the period from the date of issuance through 3 March 2012, unless announced otherwise. Amendments to this BAA will be posted to the websites listed above when they occur. Interested parties are encouraged to periodically check these websites for updates and amendments.

https://www.fbo.gov/ https://www.medicalcountermeasures.gov/ http://www.phe.gov/

Pre-Proposal Conferences:

Note: Offerors are encouraged to attend one or both of the conferences. However, the conference will have limited seating.

Pre-proposal Conference #1: March 23rd, 2011, 2:00 – 4:00PM EST, for all research areas of interest.

200 Independence Avenue S.W.

Hubert H Humphrey Building 7th floor Room 725A Washington, DC 20201

Please note the following regarding the pre-proposal conference:

1. Enter the Humphrey Building at the Independence Avenue Street entrance.

2. Arrive 30 minutes early to allow time to clear security.

3. Bring your identification

4. The closest metro stop is Federal Center SW

5. Attendance is limited to a maximum of two (2) people per company. Email the names of your attendees to CBRN-BAA-11@hhs.gov by Friday, March 11th, 2011.

6. Tape recorders and videos are prohibited.

7. Presentation material from the conference will be posted on FedBizOpps in an amendment to the BAA following the pre-proposal conference

Pre-proposal Conference #2: A second pre-proposal conference is anticipated on or about June 8, 2011 in San Diego, CA and will be announced in a subsequent FedBizOpps amendment to this BAA.

Questions from industry may be emailed to CBRN-BAA-11@hhs.gov no later than March 11, 2011. Submitted questions will be addressed during the March 23rd Pre-Proposal Conference.

NOTE: For those who are unable to attend, please use the following dial-in information: 1-800-

369-2101 Participant code # 45746

* Be advised that in order to obtain security clearance, advanced notification must be provided by all attendees who are not United States citizens.

Part I: Research Areas of Interest

Through this solicitation, ASPR seeks to support advanced research and development strategies in the following research areas of interest. Offeror shall review Part II: Research and Technical Objectives. This section presents the CBRN-related technical objectives that BARDA seeks to achieve through this BAA.

Area of Interest #1: Vaccines

1.1 Development of new vaccine/adjuvant formulations; use of approved or novel adjuvants in conjunction with a specific vaccine to achieve desired improvements like enhanced efficacy, antigen-sparing or lower adverse effects.

1.2 Development of desired capability improvements for vaccine attributes such as enhancements in formulation and delivery methods, time to protection, duration of protection, product stability and shelf-life.

1.3 Product development of a vaccine/adjuvant candidate formulated for a specific application including non-clinical, clinical development, manufacture at pilot scale under GMP; process development and scale up including fill-finish; assay methods for drug substance and product release, stability, and characterization.

Technical Point of Contact: Dr. Eric Espeland; eric.espeland@hhs.gov

Area of Interest #2: Antitoxins and Therapeutics

2.1 Development of a multivalent botulinum toxoid for hyper-immune plasma production.

2.2 Development of peptide or small molecule antitoxins, and other novel compounds, with innovative formulations offering enhanced long-term stability.

2.3 Development of monoclonal anthrax antitoxins including non-clinical, completion of a phase 1 trial; development of a phase 2 clinical development, manufacture at pilot scale under GMP;

process development and scale up including fill-finish.

2.4 Development of novel formulations of monoclonal anthrax antitoxins.

2.5 Development of monoclonal antibody treatments and other therapeutics for agents of viral hemorrhagic fevers.

Technical Point of Contact: Dr. Stephen Morris; stephen.morris@hhs.gov

Area of Interest #3: Antimicrobial Drugs

The page limit for submissions in this area of interest may differ from other areas – all other specifications in Part IV: Proposal Preparation and Submission, Section 2: Stage 1 Quad Chart and White Paper Preparation apply. Initial submission is limited to: a cover page; a one-page mailto:narayan.iyer@hhs.gov mailto:stephen.morris@hhs.gov

Quad Chart; a one-page integrated product development timeline /; task overview; a White Paper not to exceed ten (10) pages and an addendum (not to exceed three (3) pages).

In accordance with the Pandemic and All-Hazards Preparedness Act of 2006 (PAHPA), BARDA has the responsibility to ensure that the United States has a sufficient supply of vaccines and drugs to respond to public health emergencies caused by pandemic influenza, emerging infection diseases, and chemical, biologic al, and radiological and nuclear threats. BARDA recognizes the dual utility of antimicrobials for the treatment and prevention of diseases caused by bacterial and viral threat agents, and clinically relevant emerging and drug resistant pathogens. Therefore, BARDA is actively seeking to support product development that builds synergy between threat agent and non-biodefense applications to maximize return on research investment.

The scope of this area of interest permits the following:

Clinical studies to support non-biodefense indications Additional work (e.g. manufacturing methodology development, assay development and validation) to support non-biodefense indications.

While non-biodefense studies may be supported, the pursuit of indications for biological threat agents is mandatory to be considered for award. Furthermore, the demonstration that any proposed, non-biodefense activities support ultimate readiness for biodefense (e.g. clinical safety data, manufacturing process improvement, etc.) will improve the competitiveness of proposals.

3.1 Development of novel small molecule antiviral candidates with activity against one or more biodefense threat agents (Ebola, Marburg, Junin, and Variola viruses).

3.2 Development and testing of antibiotics that are in advanced development (Phase I clinical trial ongoing or completed) for post-exposure prophylaxis (PEP) and treatment efficacy against multiple biodefense threat agents (Bacillus anthracis, Yersinia pestis, Francisella tularensis, Burkholderia mallei and Burkholderia pseudomallei) applying relevant aerosol challenge models. For mouse and non-human primates (NHPs), PEP is defined as administration of the candidate antibiotic a minimum of 24 hours post-exposure. For murine studies, treatment (delayed dosing) is defined as administration of the antibiotic 42 hours post-exposure. For NHP studies, treatment is defined as the administration of the antibiotic following an alteration in a physiologically relevant indicator (trigger) that is strongly correlated to the development of illness (e.g. fever, blood pressure, heart rate, positive blood culture or PCR postive, etc). Irrespective of the trigger for treatment used, all animals tested must be screened for a positive blood culture.

3.3 Repurposing or combining currently approved antivirals or antibiotics for prophylactic, PEP or therapeutic use against multiple biodefense threat agents (a single agent is permitted in the case of antivirals only). Repurposing currently approved pharmaceuticals originally developed for other indications, provided that the proposal can document the necessary sponsorship to obtain a label change. Testing parameters employed should be similar to those described in section 3.2.

3.4 Determination of antibiotic regimens or combinations which are capable of treating Burkholderia mallei and Burkholderia pseudomallei infections in relevant animal models.

3.5 Provision of a task order-driven, in-vitro, and murine model testing service to evaluate early stage antimicrobial drug candidates directed against infection with Gram (-) bacterial threat agents. This would include the development and testing of intravenous or intramuscular formulations for Yersinia pestis, Francisella tularensis, Burkholderia mallei, and Burkholderia pseudomallei.

Technical Point of Contact: Dr. Joseph Larsen; joseph.larsen@hhs.gov

Area of Interest #4: Radiological/Nuclear Threat Medical Countermeasures

4.1 Development of mitigators or treatments for subsyndromes associated with Acute Radiation Syndrome (ARS) and the Delayed Effects of Acute Radiation Exposure (DEARE), arising from exposure to ionizing radiation. Treatments that have efficacy when administered no earlier than 24 hours post irradiation are of particular interest. Subsyndromes of interest include:

Neutropenia Thrombocytopenia Gastrointestinal Skin (Cutaneous) Lung (Pulmonary) Kidney (Renal) Brain (central nervous system)

4.2 Development of Decorporation agents (isotopes of interest: Co-60, Cs-137, U-235/238, Pu- 238/239, Sr-90, Am-241, Po-210, other transuranics) or new formulations of existing countermeasures (e.g., improved ease of administration).

Technical Point of Contact: Dr. Ronald G. Manning; ronald.manning@hhs.gov

Area of Interest #5: Chemical Threat Medical Countermeasures:

Area of interest #5 includes medical countermeasures that protect the civilian population from the acute health effects of chemical threats, are easy to administer and rapidly effective as post-exposure therapies. The medical countermeasures should also be safe and effective in the entire population, including infants, children, adolescents, elderly, pregnant women and immunocompromised individuals. Specific areas of interest within Chemical Threat Medical Countermeasures include:

5.1 Nerve Agents:

5.1.1 Development of medical countermeasures (MCM) such as an improved anticonvulsant to replace or supplement diazepam, (faster acting after intramuscular administration; better efficacy, particularly after seizures are established; better efficacy in children).

5.1.2 Development of a neuroprotectant to prevent and treat hypoxic and/or excitotoxic brain damage.

5.1.3 Development of an improved acetylcholinesterase reactivator to replace pralidoxime chloride (e.g., broad spectrum; centrally acting) mailto:joseph.larsen@hhs.gov mailto:ronald.manning@hhs.gov

5.1.4 Development of an improved anticholinergic to supplement atropine (longer acting and centrally acting).

5.1.5 Development of new formulations of existing antidotes (more easily administered;

faster acting).

5.1.6 Development of easily administered and rapidly effective countermeasures that can be used by first responders dealing with large numbers of exposed individuals. Ease of administration in mass casualty situations should take into account the practical limits of injected medications versus inhaled, intranasal and sublingual administration. These alternative routes may fail if persons have profuse respiratory secretions. Autoinjector intramuscular injection may continue to be a preferred route of administration for many compounds under most circumstances.

5.1.7 Development of chemical decontamination solutions for use on intact /or injured human skin (improved efficacy compared to soap and water).

5.2 Pulmonary Agents: Development of anti-inflammatory drugs and other medical countermeasures to treat and prevent lung damage from exposure to agents such as chlorine and phosgene.

5.3 Vesicants: Development of medical countermeasures that limit harmful aspects of the inflammatory response following exposure to vesicating agents such as mustards and Lewisite, including topical (skin and eye) and systemic preparations.

5.4 Blood/Metabolic Agents: Development of medical countermeasures to treat poisoning from agents such as cyanides and fluoroacetates under those circumstances where response personnel are immediately present during the limited time between exposure and fatal outcome.

5.5 Toxic Industrial Chemicals and Emerging Threats: Development of medical countermeasures that protect from a wide range of unconventional threats in response to new population threat assessments.

Technical Point of Contact: Dr. Ed Wakayama; ed.wakayama@hhs.gov

Area of Interest #6: Diagnostics: Design and production of the system in area of interest #6 must be compliant with U.S. Quality Systems Regulations (21 CFR Part 820)

Bio-agent Diagnostics:

Bio-treat pathogens of interest (listed alphabetically): Bacillus anthracis (Anthrax), Botulinum toxin (Botulism), Burkholderia mallei (Glanders) and Burkholderia pseudomallei (Melioidosis), Filoviruses ( Ebola & Marburg), Francisella tularensis (Tularemia), Junin virus (Argentine hemorrhagic fever), Rickettsia prowazekii (Typhus), Variola virus (Smallpox), Yersinia pestis (Plague)

6.1 Development, clinical evaluation, and/or agency clearance of rapid in vitro diagnostic assay systems, to detect or differentiate specific bio-threat pathogens or toxins of interest in a variety of relevant clinical matrices. The assay system should enable early differential diagnosis of disease with high predictive value. Systems should incorporate integrated sample preparation/processing and results-analysis software, if applicable, for ease of use by non-expert personnel at point-of-care.

mailto:ed.wakayama@hhs.gov

6.2 Development and evaluation of new analytical methods to quantitate circulating toxin levels.

6.3 Development, clinical evaluation, and/or agency clearance of stable diagnostic reagents to detect or differentiate specific bio-threat pathogens or toxins of interest in a variety of relevant clinical matrices for use with existing diagnostic instrument platforms which have a large number of US Clinical lab placements. Reagents should ideally be room-temperature stable with greater than two years shelf life.

6.4 Development and clinical evaluation of simple, reliable sample collection and sample preparation methods/systems.

Biodosimetry Diagnostics:

6.5 Development of a dosimetry self assessment tool for exposures to ionizing radiation at or greater than 2 Gy.

6.6 Development, clinical evaluation, and/or agency clearance of rapid diagnostic systems for determining white blood cell counts from whole blood. These systems should be portable and designed for ease of use by non-expert personnel at point-of-care.

6.7 Development of a rapid point-of-care diagnostic or centralized high-throughput assay system for assessing absorbed doses of ionizing radiation in the range of 0.5 Gy to 10 Gy that has a viable assessment signal at least 24 hours after exposure and that persists up to one month after exposure. The assay system should enable early differential diagnosis of exposure with high predictive value. It is preferred for high throughput assays to be used with existing diagnostic instrument platforms which have a large number of US Clinical lab placements.

6.8 Development of an improvement on the current “gold standard” for assessing absorbed doses of ionizing radiation (the dicentric chromosomal assays (DCA)) in terms of ease of use, time for performance, statistical certainty of dose, improved signal, and biomarker lifespan.

Chemical Agent Diagnostics:

6.9 Development of medical diagnostic tools that are sensitive, specific, rapid and easily transferable to hospitals and clinical laboratories using available or emerging technological platforms to detect or differentiate the presence of or exposure to specific chemical threat agents or toxic industrial chemicals (TICs) in a variety of relevant clinical matrices. Threat agents to be considered include chemical nerve agents, pulmonary agents, vesicants (mustard agents), blood/metabolic agents, TICs, and emerging threats. The tools should enable early differential diagnosis of exposure with high predictive value. Design and production of the tool/system must be compliant with U.S. Quality Systems Regulations (21 CFR Part 820).

Technical Point of Contact: Mr. Rodney Wallace; rodney.wallace@hhs.gov mailto:rodney.wallace@hhs.gov

Part II: Research and Technical Objectives The topics listed below exemplify some of the typical developmental activities in the areas of non-clinical research, manufacturing, clinical evaluation, project management, and regulatory strategy contained in a typical drug, biologic or device development effort. This information is provided to assist and guide Offerors in preparing their Statement of Work (SOW). Offerors shall submit a SOW in their proposal that addresses these topics as appropriate. Provide as much detail as may be necessary to fully explain the proposed technical approach or method.

For drug and biologic medical countermeasure development efforts, Offerors shall propose a Statement Of Work (SOW) preferred to be consistent with activities between Integrated Technology Readiness Levels (TRLs) 6 to 7 (see https://www.medicalcountermeasures.gov/Integrated_TRLs.aspx). For Chemical Radiological and Nuclear (CRN) Research Areas 4 and 5, Offerors shall propose a SOW that is consistent with activities occurring at TRL 3 or greater (see Attachment 1). For diagnostics, Offerors shall propose a SOW that is consistent with activities occurring at TRL 4 or greater (see Attachment 1).

Proposal preparation and submission instructions are contained in Part IV.

A. Development Approach:

1. Non-Clinical Research and Development Representative Activities include but are not limited to:

a. Screening of small molecule libraries for antitoxin/antimicrobial/antiviral activities (for already approved or licensed product).

b. Evaluating the safety, immunogenicity, efficacy, pharmacokinetics / pharmacodynamics, bioavailability, solubility, formulation, dose, route and schedule of the medical countermeasure using both in vitro and animal models following Good Laboratory Practice guidelines (GLP: as defined in the U.S. Code of Federal Regulations -21CFR Part §58), as and when appropriate.

c. Development of analytical methods and assays appropriate for product characterization and product release, including tests for the identity, purity, potency, and stability of the bulk drug substance and final drug product. Offerors shall identify a stable source and availability of reagents and reference standards for these assays required.

d. Development of Validation Protocol for analytical and assay methods to defining product manufacturing control, performance, potency and product stability indication.

2. Process Development, Formulation, and Manufacturing Development Representative Activities include but are not limited to:

a. Development of master and working cell banks under Good Manufacturing Practice guidelines (GMP: as defined in the U.S. Code of Federal Regulations –

21 CFR §211).

b. Process development activities to increase efficiency, yield, quality, and reduce the variability and risk factors in the manufacture of the drug substance and drug product.

c. Formulation development to evaluate combinations of excipients and their influence on the target product profile and stability.

e. Manufacture of non-GMP and of GMP pilot lots of candidate product in amounts sufficient to carry out required/proposed non-clinical and Phase 1 and/or Phase 2 clinical trials.

f. Identification of Critical Quality Attributes (CQA) and Critical Process Parameters.

g. Manufacturing scale-up plan to lead to consistency lot manufacturing of the candidate product.

h. Process flow for personnel, material and waste disposal.

i. Proposed packaging design and execution of fill-finish of final drug product.

j. Design of stability testing plan and conduct of stability studies on bulk and final product.

k. Develop a Risk Evaluation and Mitigation Strategy or similar risk mitigation strategy proposal

l. Manufacturing/Testing facility plan to support phase I through commercial scale product supply

3. Clinical Evaluation Representative Activities include but are not limited to:

a. Design and conduct of Phase 1 clinical trials to evaluate the safety and pharmacokinetics of the therapeutic candidate/product in humans in accordance with Good Clinical Practice guidelines (GCP: as defined by 21 CFR §312 and ICH Guidelines document E6.

b. Design and conduct of a Phase 2 and/or Phase 3 clinical trial in accordance with all Federal regulations and GCP guidelines.

B. Management Approach:

1. Integrated Product Development Plan (IPDP) Representative Activities include but are not limited to:

a. Activities and stages of product development that the Offeror is proposing to perform under contract funding in a project plan that indicates the base period and option period activities and includes all of the functional areas of development listed below.

b. A detailed description of the experimental design, including the rationale for experimental approaches, and a description of alternative approaches to be employed if these methods do not achieve the defined goals.

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

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

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

f. A listing of key personnel (including proposed consultants) who possess the necessary education, training, and experience to successfully perform the work identified in the technical proposal and their resumes

g. A staffing plan that indicates personnel (in-house and contracted) resources and the percentage of time to be dedicated to perform the work.

h. A clear and comprehensive regulatory master plan that focuses on the crucial pathway integrating all products, risk evaluation and mitigation at all development stages, non-clinical and clinical testing, and manufacturing activities using the most current and available information, including documented and time-relevant consultation with FDA.

i. Establishment and filing of regulatory submissions to the relevant FDA center.

j. A plan for additional studies to support future filing for FDA-approval/clearance.

k. Summary of any prior communication with the FDA relevant to the product development; summary of audits and inspections.

l. Tentative schedule of regulatory milestones.

m. Potential Plan for consideration of an Emergency Use Authorization (EUA) of a medical product (http://www.fda.gov/oc/guidance/emergencyuse.html)

n. A work breakdown structure (WBS) that is discernable and consistent. It may include data at the cost account level or at the work package level or at a lower level if there is significant complexity and risk associated with the task

o. An approach for tracking milestones, costs, risks, subcontractor effort (if applicable), deliverables and proposed internal procedures for assuring timely responses to the Government‟s needs on any resulting contract.

p. An approach for performance measurement that shall, include establishing an initial plan; defining measurable parameters; defining how these parameters relate to cost and schedule impacts; their approach in providing a detailed schedule that generates a critical path for the project; and a description of the cost-accounting system used or intended to be used based on budget estimates to monitor all costs related to the contract award for both prime- and sub-contractors on a real time bases.

Within fourteen (14) calendar days of the effective date of the BAA award, the Offeror shall submit an updated IPDP which shall be approved by the Project Officer and the Contracting Officer prior to initiation of any activities related to their implementation.

During the course of contract performance, in response to a need to change the IPDP, the Offeror shall submit a Deviation Report. This report shall request a change in the agreed-upon Plan and timelines. This report shall include:

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

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

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

The Offeror shall carry out activities within the contract SOW only as requested and approved by the Contracting Officer, and may not conduct work on the contract without prior approval from the Contracting Officer, including initiating work that deviates from the agreed-upon IPDP.

2. Target Product Profile (TPP): In their proposal, Offerors shall discuss the TPP of their proposed candidate medical countermeasure. Offerors should use the template in Attachment 7 to develop the TPP.

http://www.fda.gov/oc/guidance/emergencyuse.html

a. The intended use or indication of the proposed medical countermeasure.

b. The intended product profile (strength, quality, purity and identity) noting the performance specifications and features of the medical countermeasure that provide benefit.

c. A description of the medical countermeasure as it is currently configured.

d. A description of the manufacturing process including expected formulation

(configuration) of the final product.

e. A description and developmental status of the assays for product release which provide characterization, strength, identity, and purity, as well as any needed assays for product activity and efficacy.

f. Discussions with appropriate FDA reviewers that is relevant to development activities for the proposed medical countermeasure, including plans for generating data to support an Investigational New Drug (IND), Biologics License Application (BLA) or New Drug Application (NDA), Pre-Market Approval and/or 510(k) application: summary of any prior, time-relevant communication with FDA relevant to the product development for the indication noted; summary of audits and inspections relative to the current development or proposed manufacturing (Including at key sub-contractors) of the intended product.

3. Contractor provided Facilities, Infrastructure and other Resources Representative Activities: Depending on the stage of development of the candidate product, this may include but is not limited to:

a. Current facility design including quality control labs for testing & release, laboratory areas supporting formulation and assay development, manufacturing process flow, and animal studies.

b. Major equipment and layout (preliminary piping and instrumentation drawing).

c. Manufacturing capacity expansion plans to match the proposed manufacturing scale up.

d. Overview of the management of Quality Systems at the facility.

e. List of capabilities for clinical activities conducted in house and at contract research organizations.

f. Qualified animal facilities where GLP studies would be conducted and appropriate certifications for humane care and use of vertebrate animals.

Detailed instructions on proposal preparation and submission are contained in Part IV.

g. The handling, storing and shipping of potentially dangerous biological and chemical agents, including Select Agents, under biosafety levels required for working with the biological agents under study. Detailed instructions on proposal preparation and submission are contained in Part IV.

h. Validation master plan for key equipment, analytical methods and manufacturing process.

4. Security Plan Representative Activities include but are not limited to:

a. The establishment of a comprehensive security program that provides a security plan for the overall protection of personnel, information, data, and facilities.

b. Security administration, as an element of the security program that address threat and risk assessments and related policies and procedures for personnel security, physical security, information security, information technology.

c. Security management, as an element of the security program that describe each element of security: physical, operations, personnel, information, information technology, transportation; and related training, auditing, and reporting requirements.

Additional information for Security Plan requirements are described in Part IV Section 4, para H and in Attachment 3

Part III: Reporting Requirements and Deliverables

Some reports and other deliverables are relevant to specific activities that may or may not be performed during the contract period of performance. The Contractor, the Project Officer and the Contracting Officer shall agree in the final contract negotiations on which reports and other deliverables are relevant and shall be required as deliverables as determined in the negotiated

SOW.

As part of the work to be performed under this BAA, the Contractor shall prepare and deliver the following reports throughout the period of performance. For all reports the Contractor shall submit two (2) paper copies and one (1) electronic copy to the Contracting Officer.

Reports:

1. Technical Progress Reports

On the fifteenth (15) day of each month for the previous calendar month, the contractor shall submit to the Project Officer and the Contracting Officer a Technical Progress Report. The frequency of Technical Progress Reporting will be determined by the Contracting Officer and Project Officer during negotiations of the contract. The format and type of Technical Progress Report and Executive Summary will be provided by the Project Officer. The technical Progress Reports will include project timelines and milestones summaries of product manufacturing, testing, and clinical evaluation. A Technical Progress Report will not be required for the period when the Final Report is due. The Contractor shall submit one copy of the Technical Progress Report electronically via e-mail. Any attachments to the e-mail report shall be submitted in Microsoft Word, Microsoft Excel, Microsoft Project, and/or Adobe Acrobat PDF files. Such reports shall include the following specific information:

a. Title page containing: Technical Progress Report, the contract number and title, the period of performance or milestone being reported, the contractor‟s name, address, and other contact information, the author(s), and the date of submission;

b. Introduction/Background: An introduction covering the purpose and scope of the contract effort;

c. Progress: The report shall detail, document and summarize the results of work performed, test results, milestones achieved during the period covered and cumulative milestones achieved. Also to be included is a summary of work planned for the next two (2) reporting periods on a rolling basis;

d. Issues: Issues resolved, new issues and outstanding issues are enumerated with options and recommendation for resolution. An explanation of any difference between planned progress and actual progress, why the differences have occurred, and, if progress activity is delinquent, then what corrective steps are planned. Revised timelines are provided.

e. Invoices: Summary of any invoices submitted during the reporting period.

f. Action Items: Summary table of activities or tasks to be accomplished by certain date and by whom.

g. Distribution list: A list of persons receiving the Technical Report

h. Attachments: Results on the project are provided as attachments

2. The Executive Summary, which shall accompany each Technical Progress Report, will be formatted in Microsoft Power Point presentations and include the following:

a. Title page containing Executive Title, the contract number and title, the period of performance or milestone being reported, the contractor‟s name and the date of submission;

b. Project Progress presented as milestone events, test results, tasks, and other activities achieved during the reporting period as talking point bullets;

c. Project issues presented headings and each item as a talking point bullet.

3. Final Report: By the expiration date of the contract, the Contractor shall submit a comprehensive Final Report that shall detail, document, and summarize the results of the entire contract work. The report shall explain comprehensively the results achieved.

A draft Final Report will be submitted to the Project and Contracting Officers for review and comments, then the Final Report original, four copies, and an electronic file shall be submitted to the Project and Contracting Officers for distribution to the Program office.

4. These reports are in addition to other reports and deliverables that may be required in the final negotiated SOW as referenced above.

Meetings and Conferences:

The Contractor shall participate in regular meetings to coordinate and oversee the contract effort as directed by the Contracting and Project Officers. Such meetings may include, but are not limited to, meeting of all Contractors and subcontractors to discuss clinical manufacturing progress, product development, product assay development, scale up manufacturing development, clinical sample assays development, pre clinical/clinical study designs and regulatory issues; meetings with individual contractors and other HHS officials to discuss the technical, regulatory, and ethical aspects of the program; and meeting with technical consultants to discuss technical data provided by the Contractor.

Monthly teleconferences between the Contractor and subcontractors and BARDA shall be held to review technical progress. BARDA reserves the right to request more frequent teleconferences and face-to-face meetings depending on the criticality and nature of the work being performed. Contractor will receive feedback from BARDA during the monthly teleconference regarding contract performance. The Contractor will have an opportunity to respond and provide recommendations / remediation plan during the execution of the contract.

Regulatory and Quality Management:

FDA Submissions and meetings:

a. The contractor shall forward the dates and times of any meeting with the FDA to BARDA and make arrangements for appropriate BARDA staff to attend FDA meetings.

b. The contractor shall provide BARDA the opportunity to review and comment upon any documents to be submitted to the FDA. The contractor shall provide BARDA with five (5) business days in which to review and provide comments back to the contractor.

c. The contractor shall forward the initial draft minutes and final draft minutes of any formal meeting with the FDA to BARDA.

d. The contractor shall forward the final draft minutes of any informal meeting with the FDA to BARDA.

e. The contractor shall forward Standard Operating Procedures (upon request from Project Officer/Contracting Officer).

f. The contractor shall provide upon request animal study and/or other technology packages developed under this contract. Packages shall include complete protocols and critical reagents for animal models developed and/or improved with contract funding.

g. The contractor shall provide upon request raw data and/or specific analysis of data generated with USG funds.

Audits / Site Visits:

FDA Audits Within thirty (30) calendar days of an FDA audit of Contractor or subcontractor facilities, the Contractor shall provide copies of the audit findings, final report, and a plan for addressing areas of nonconformance to FDA regulations and guidance for GLP, GMP or GCP guidelines as identified in the final audit report.

BARDA Audits The United States Government (USG) reserves the right to conduct an audit of the Contractor with 48 hours notice. The USG reserves the right to accompany the Contractor on routine and for-cause site-visits/audits of subcontractors. At the discretion of the USG and independent of testing conducted by the Contractor, BARDA reserves the right to conduct site visits/audits and collect samples of product held by the Contractor and subcontractors.

Part IV: Proposal Preparation and Submission

Section 1: The Application Process The application process is in two stages as follows:

Stage 1: Complete a cover…