BAA Amendment 3 TRL and QA

AMENDMENT TO BARDA BROAD AGENCY ANNOUNCEMENT

ADVANCED DEVELOPMENT OF CHEMICAL, BIOLOGICAL, RADIOLOGICAL, AND NUCLEAR MEDICAL COUNTERMEASURES

Broad Agency Announcement Number:

BAA-BARDA-09-34

Amendment Number:

Three (3)

Amendment Posting Date:

May 13, 2009 Issued By:

Biomedical Advanced Research and Development Authority (BARDA)

330 Independence Ave., SW, Room G640

Washington, D.C. 20201

Point of Contact:

Primary: Glynis Fisher, Contract Officer glynis.fisher@hhs.gov

Alternate: Jeannett Jackman, Contract Specialist jeannett.jackman@hhs.gov

SUMMARY OF CHANGES

A. PURPOSE: The purpose of this Amendment is to replace Attachment 1, (Draft) Technology Readiness Level (TRL) Definitions for Drugs and Biologics and Attachment 2, (Draft) Technology Readiness Level (TRL) Definitions for Medical In-Vitro Diagnostic Devices, pages 38-42 in its entirety. This amendment also posts questions received from industry and the government’s responses from the Pre-Proposal Conference conducted March 24, 2009

1. The revised Integrated TRL’s can be found at the following link: https://www.medicalcountermeasures.gov/Integrated_TRLs.aspx. The revised Product Development Tools can be found at the following link: https://www.medicalcountermeasures.gov/TRLs_for_PDTs.aspx.

2. The date specified for receipt of white papers and proposals remains unchanged. Except as provided herein, all terms and conditions of the Broad Agency Announcement remain unchanged.

BAA-BARDA-09-34 - BARDA BROAD AGENCY ANNOUNCEMENT (BAA) FOR THE ADVANCED DEVELOPMENT OF CHEMICAL, BIOLOGICAL, RADIOLOGICAL, AND NUCLEAR MEDICAL COUNTERMEASURES

QUESTIONS AND ANSWERS FROM PRE-PROPOSAL CONFERENCE #2

TUESDAY,

MARCH 24, 2009

1. The BAA states that applicants should submit countermeasure development efforts consistent with TRL 6 to 7. However, Area of Interest #3 (Antimicrobial Drugs), includes the objective 3.1 Screening of small molecule libraries and subsequent development of promising lead compounds. Screening, lead optimization, and lead development could be considered to be TRL 3, 4, and 5 activities, respectively. Does BARDA intend for all efforts under 3.1 to be of TRL 6 to 7? How does BARDA view the activities of “screening” and “development of promising lead compounds” as applying to TRL 6 and 7 definitions?

The BAA was established to cover all current and potential research areas. BARDA intends to initially fund programs that fill a priority need as identified in the 2007 PHEMCE Implementation Plan for CBRN Threats and are at an advanced stage of development. There is no restriction on submitting quads and white papers from programs at earlier stages. However, with limited funds available, programs that address requirements identified in the 2007 PHEMCE Implementation Plan for CBRN Threats and are at a more mature stage will most likely receive funding from BARDA.

2. Security Planning: Can BARDA provide further clarity on or examples of what may be considered “sensitive BARDA program information” as it relates to an applicant’s proposed work plan, and at what stages of an applicant’s work plan access to such information might be required? What are the elements that BARDA will consider in an application for a waiver from these requirements? Will BARDA consider Security Plans that include some, but not all of the measures described in Attachment #4?

All companies should have a security plan in place as a part of good business practices. Any information that is considered proprietary should be protected even if not under contract with the USG. A waiver can be requested if the applicant feels their program/product is in such an early stage of development that theft or loss of the information would generate no risk to the USG program. Potential contractors can submit security plans that include certain elements under attachment #4 and request waivers for others. The waiver should be submitted to the Contracting Officer and explained in detail, why the waiver is being requested.

3. With regard to the hematopoietic (bone marrow) and gastrointestinal countermeasure programs, we understand that BARDA is supporting the advanced development of the hematopoietic area, while the Department of Defense is supporting the gastrointestinal area. Although both of these areas are listed in the BAA (Areas of Interest #4, page 8), is there a bias towards hematopoietic that should be emphasized in a proposal, with the gastrointestinal as a secondary indication?

There is no bias towards hematopoietic injury with this solicitation. BARDA is interested in all aspects of acute radiation syndrome listed in the areas of interest; these are often not separate and distinct but rather represent a continuum of injury with increasing absorbed dose. HHS and DOD are coordinating efforts to support development of the suite of FDA licensed/approved products that will be needed to address the complexity of Acute Radiation Syndrome (ARS) injury. In general, DOD has focused on development and acquisition programs for the gastrointestinal ARS syndrome, while HHS recent activities have been focused on addressing the hematopoietic ARS syndrome. In this way, Federal resources can be most effectively leveraged to ensure appropriate preparedness in both the civilian and military populations for radiological and nuclear threats. However, the nature of radiation injury is such that this separation of syndromes is somewhat arbitrary and HHS and DoD communicate closely regarding their efforts to address both syndromes.

4. If an Offerors countermeasure agent is already in phase 1 clinical studies (for development towards non-CBRN uses) and the agent has positive effects in multiple threat areas (e.g. radiologic, chemical, antimicrobial) and is at different stages of non-clinical development in these threat areas, is it advisable for the Offerors to prepare a single full proposal covering all of the threat areas (but prioritized and tracked separately within) or to apply for each threat area in separate full proposals? Should the Offerors submit separate pre-proposals?

The Offerors should submit separate quad charts and white papers for each indication, and correspondingly separate full proposals for any white papers selected to submit full proposals.

5. There appears to be no requirement in the proposal to have had any prior interactions with FDA regarding a pre-IND meeting or any guidance on the development of an approvable NDA/BLA package. There is a clear requirement that regular interaction with FDA is critical in the proposal. Would you confirm this, and comment on the strength of a proposal if FDA guidance is or is not obtained prior to submission of a full proposal.

As stated in the BAA, BARDA is targeting TRL 6-7. At this point in development the sponsor should have developed a Target Product Profile and may have shared this information with FDA at a pre-IND meeting. Proposals that are at this stage of development and meet the goals of the PHEMCE Implementation Plan for CBRN Threats will most likely be considered for funding. The special instructions that will be issued for research areas listed in the BAA may also request documentation highlighting FDA interactions.

6. Is there any requirement for in-house (vs. subcontracted) conduct of any of the advanced development studies for which funding will be sought? Will it be acceptable for the Offerors to contract out all GLP, GMP and GCP studies, as well as rely on industry experts in these areas as consultants to assist with the product development process? Is the use of contract research organizations and contract manufacturing organizations outside of the US acceptable if these entities are documented to meet GLP and GMP compliance? The same question as to clinical CROs outside of the US?

There are no requirements for in-house vs. subcontracted CRO or CMOs associated with a proposed program under the BAA. The Offeror may propose contracting out studies as part of the scope of their proposal. BARDA suggests to Offerors with a significant amount of activities being conducted by subcontractors to put in place a robust project management plan and contracts that will enable a high degree of programmatic oversight.

7. From BARDA’s (but not necessarily FDA’s) perspective, would a non-US patient population (e.g. European) be acceptable to support phase 1 studies for an indication (e.g. radiation countermeasure) where no phase 2 study could be ethically conducted?

Sponsors should seek guidance from FDA on acceptability of non-US patient-based population for clinical studies.

8. Independent of FDA’s requirements, does BARDA have guidelines on the size of a phase 1 clinical study for the radiation countermeasure indication and the types of subpopulations that would need to be included (e.g., elderly, immune compromised, children) ?

BARDA does not provide guidelines on clinical trial size nor the type of subpopulations appropriate for studies. The power of any trial and types of subpopulations should be vetted with the appropriate FDA review division prior to conducting the trial.

9. In which indications in the BAA would a phase 2 study be appropriate?

Phase 2 studies are appropriate in all areas upon concurrence of clinical protocols and design from the FDA.

10. What are the definitions of subsyndromes for skin, lung, kidney, and brain injury after radiation emergencies? What screens can be recommended to evaluate efficacy?

Part 1: Acute Radiation Syndrome (ARS) is the medical consequence of exposure of the whole body (or large proportion of the body) to a relatively large dose of radiation (above approximately 1-2 Gy or 100- 200 rad) usually delivered from an external source over a period of seconds to days. ARS encompasses a spectrum of clinical changes that reflects the differing organ sensitivity to ionizing radiation. ARS is comprised of the subsyndromes named for the organ system linked most closely to cause of death (e.g. cutaneous (skin), lung, kidney, etc.)

Part 2: It is the Offerors responsibility to evaluate, with FDA guidance, the efficacy of their products.

11. At what stages of development does chemical threat medical countermeasures have to be to obtain funding by BARDA?

Please refer to the answer to question #1.

12. If a pre-proposal does not receive a favorable evaluation for continuing to a full proposal but the technology area is still of interest, will BARDA provide comments and/or assistance and can the Offerors submit a revised pre-proposal during the open submission period?

Yes, BARDA intends to provide comments/assistance to Offerors through the white paper and proposal process. Offerors may resubmit a revised white paper at any time prior to Dec 31, 2009.

13. What screens are recommended for a neuroprotectant to evaluate efficacy in preventing and treating hypoxic and/or excitotoxic brain damage?

Please refer to Part 2 of the answer to question #10

14. What screens are recommended to evaluate efficacy in treating and preventing lung damage from exposure to chemical agents?

Please refer to Part 2 of the answer to question #10

15. What screens are recommended to evaluate efficacy in protecting against vesicating agents?

Please refer to Part 2 of the answer to question #10

What screens are recommended to evaluate efficacy in protecting against blood and metabolic agents like cyanides and fluoroacetates?

Please refer to Part 2 of the answer to question #10

16. The BAA mentions orthopoxvirus and hemorrhagic fever specifically but does not mention bacterial threats such as anthrax and plague. Is there interest in proposals for screening for antibacterial agents?

Please refer to Part 1 of the BAA for details on the research areas of interest. The BAA also calls for screening of small molecule libraries for activities of “other Biodefense agents.” Please refer to the HHS PHEMCE Implementation Plan for CBRN Threats for the list of those Biodefense agents against which medical countermeasures are sought. As described in this Plan, broad spectrum antibiotics against anthrax and plague are a high priority for HHS.

Link: http://www.hhs.gov/aspr/barda/phemce/enterprise/strategy/index.html

17. Information in the BAA indicates a funding decision will be made within 180 days of receipt of the Phase II proposal. For awarded proposals, when can funding begin?

Funding will be initiated after contract award.

18. The BAA refers to priorities and strategies as described in the Federal Register / Vol. 72, No. 53 / Tuesday, March 20, 2007 / Notices. Midterm strategies are targeted for FY 09-13, and it is stated that support needed to “pull promising countermeasures through the development pipeline” will be given. Are there plans to execute on this strategy in 2009 in the field of antibacterials? Note: there are currently few new late stage development antibacterials that address a Biodefense bacterial infection.

BARDA is interested in funding research in antibacterials. Broad spectrum antibiotics will be a focus of our funding efforts in the coming years. While the focus of the BAA is for programs at TRL6-7; no one is discouraged from submitting a white paper. Understanding the capabilities and scope of research being conducted will assist us in planning our budgets for FY10 and beyond.

19. Is any consideration given to integrate BARDA focus on Biodefense infections with the current urgent public health issue of MRSA?

BARDA currently has no requirement to fund research in this area.

20. Given the strategy as described in the Federal Register Vol 72 notice, the screening described in the BAA would appear to represent earlier stage, DISCOVERY research. Considering the lack of novel antibacterial drugs in development, has BARDA expanded its strategy to include drugs currently in clinical development that have appropriate spectrum against Biodefense pathogens?

Please refer to the answer to question #1.

21. Concerning repurposing of currently licensed antibiotics, would combination formulations (to address spectrum and resistance) be of interest?

Yes. BARDA would consider proposals that evaluate combination formulations.

22. In the Chemical Threat Medical Countermeasure area of interest for item 5.1.4, is there a requirements document that has been developed?

No official USG requirements documents (from any threat area) have, to date, been released publicly. Instead, the medical countermeasure requirement information including size and desired product specifications, have been included as part of the Request for Proposals (RFP).

23. For the clinical diagnostic tools, is it correct that the proposal and SOW should take the technology up to the point of readiness for pre-clinical trials, but should not include pre-clinical trials?

It would be acceptable to include pre-clinical trials in the proposal and SOW.

24. Does BARDA expect that the clinical diagnostic tools developed under this BAA will proceed to pre-clinical trials? If so, will there be additional funding to support those clinical trials?

Please refer to the answer to question #1. If the technology is promising and meets earlier metrics, BARDA hopes the technology moves forward toward FDA clearance, including pre-clinical trials.

25. What is the expected period of performance for clinical diagnostic tool projects funded by BARDA?

It is anticipated that contracts awarded under this BAA will be awarded as one-year base contracts with one-year options up to 5 years. Continuation of funding after the initial year is dependent upon availability of funds and achievement of milestones.

26. Is there a limit on the funding that can be requested for one project?

The number and quantity of awards under this BAA for each fiscal year will depend on the amount of funding available to BARDA through yearly appropriations. Funding determinations will be made based on the criteria identified in the BAA and alignment with the PHEMCE Implementation Plan for CBRN Threats

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

27. Is there a specific list of bio-threats for which assays should be developed for this effort?

Please refer to the PHEMCE Implementation Plan as stated in the answer to question #26.

28. What are the clinical sample types/matrices to be tested?

Offerors are encouraged to consult with the FDA Center for Devices and Radiological Health (CDRH) for advice on appropriate sample types in considering the intended use of the device/system. There are also study reports available on appropriate test matrices for the various agents of concern.

29. Can applicants submit more than one proposal to address different subsections within a specific area of interest?

Yes, Offerors may submit multiple proposals (Quad Chart and White Paper) to the different research area of interest or within a single area of interest.

30. If an award is received, what funding contract alternatives will be available? Would cooperative agreements and/or grants be an option?

At this time BARDA will be awarding contracts; however, we anticipate being able to award both cooperative agreements and grants for programs funding on the BAA in the future. No date has been set as to when the options for cooperative agreement or grants will be available.

31. “For the Radiological and Nuclear Threat Countermeasures Research Area, is proof of concept data a requirement for an award or can awards be used to verify that a compound has applicability as a radiological/nuclear medical countermeasure?”

Programs that are at a more mature stage will be more likely to receive funding. It could be an appropriate use of funding however to show a radiological/nuclear indication for a countermeasure more advanced for a different indication

32. Will this BARDA BAA fund non-clinical small molecule drug development efforts for novel/new antimicrobials? There was some confusion with perhaps “countermeasure drugs” needing to be TLR 6 or 7 (basically clinic-ready).

Please refer to the answer to question #1.

33. Are there specific antimicrobial pathogens that have been prioritized (e.g. Yesinia pestis)?

Please refer to the PHEMCE Implementation Plan as stated in the answer to question #26.

34. How far should we propose to go with the development program under this solicitation? Just through lead optimization?

You should focus your development plan on a base year with the possibility of continuing development up to 5 years.

35. Will feedback be given to both acceptable and non acceptable white papers?

Yes, the intention is to provide feedback to all white papers submitted in response to this BAA.

36. Will the government intend to make available or share with industry the medical countermeasures requirements document?

Requirements and other documents that BARDA can share with the public are posted on the medical countermeasure website (www.medicalcountermeasure.gov) and the BARDA website (http://www.hhs.gov/aspr/barda). To learn about the overall objectives for medical countermeasure development, please see the 2007 PHEMCE Implementation Plan for Medical Countermeasures for CBRN Threats.

37. What is BARDA’s plan for providing funding for companies who already have a commercially available product and wish to partner with the government to develop a medical countermeasure using that product? What specific opportunities are available for those companies, or such companies?

BARDA reserves the right to award the contract type best suited to the nature of the work proposed and may award any appropriate contract type under the Federal Acquisition Regulation for licensed products or new medical countermeasure products that aligns with the 2007 PHEMCE Implementation Plan for Medical Countermeasures for CBRN Threats. In the future, BARDA may, also elect to make awards in the form of grants, cooperative agreements, or other transactional agreements (OTAs) as appropriate. BARDA can use either available funding or special reserve fund for procurement or potentially purchase already licensed products through the Strategic National Stockpile.

38. How would BARDA deal with the Federally Funded Research and Development Centers (FFRDC)? Would you also be looking at contracts with FFRDCS?

BARDA will work with each of the FFRDC to figure out the best contract type best suited for the nature of the work proposed and how best to structure the contracts.

39. Are submissions of multiple white papers allowed? Should we submit separate white paper if the indication is the same but the delivery method is different?

The recommendation is to submit separate white papers for each delivery method. The page limit of the white paper is 5 pages.

40. Could you comment on BARDA's view regarding interacting with the advisory component of FDA as opposed to the review component of FDA?

We can suggest reviewer points of contact for both CBER and CDER as your initial contacts.