QA' to the ARS Draft RFP vs 25Mar 2009.doc

Question and Answers in Response to

HHS-BARDA-09-33 Draft ARS RFP

Comment: Given the number of questions regarding the list of studies delineated in the RFP, BARDA wants to clarify that the list is intended to be a guide for planning purposes and that potential Offerors should consult with the appropriate division of the FDA when designing their regulatory path.

1. Can BARDA Contracting Office please confirm that the time allotted between issuance of the final RFP and deadline for submission will be on the order of 60 (sixty) days, and not the 30 (thirty) days as suggested in the draft RFP?

A. 55-60 Days will be the response period.

2. Please clarify the objective at the end of 5 years: a) have completed the process of filing a NDA/BLA for licensure by FDA; or b) have completed all regulatory, development and manufacturing activities required for FDA licensure.

A. “b”

3. Allowing only 2 representatives to attend the pre-proposal conference is limiting. Additional attendees would be valuable for the overall proposal preparation process. Offeror requests that additional representatives be permitted to attend.

A. Added the option for “space available” slots upon request.

4. Cardiovascular Toxicology Studies. It is customary to conduct preclinical cardiovascular safety/pharmacology study in one relevant species, only (rabbit, dog, other). The draft RFP refers to NHP-toxicology-cardiovascular and SAS-cardiovascular, implying cardiovascular preclinical safety/pharmacology in two species. Offeror is proposing that the request for cardiovascular safety/pharmacology be conducted in one relevant species only. Does the Contracting Office agree?

A. FDA should be consulted before trials are executed. The Offeror may propose modifications to the study list presented in the final RFP and provide justification for the modification.

5. Drug-Drug Interaction Studies. Similar to question 5 above, it is our experience that preclinical D-D interaction studies be conducted in one relevant species, only, whereas the draft RFP indicates two such studies be conducted (NHP, D-D and SAS, D-D). Offeror is requesting that D-D interaction study be performed in one relevant species, only. Does the Contracting Office agree?

A. FDA should be consulted on the design and types of study for the regulatory plan. The Offeror may propose modifications to the study list presented in the final RFP and provide justification for the modification.

6. The RFP mentioned the requirement for non-clinical efficacy study design to match the clinical age-sex weighed equivalents of the clinical setting (page 4 C.3.c). Does the clinical age range in this requirement refer to ages 18 to 64 years, which does not include the pediatric or geriatric population? The contractor is proposing non-clinical efficacy studies to be performed in young adult animals not juvenile or aged animals. Pediatrics and geriatrics populations will be studied in safety/PK studies in human clinical setting. Is this acceptable to HHS BARDA?

A. Yes, this is acceptable to BARDA.

7. What does age-sex weighted equivalents mean in the context of non-human efficacy study design?

A. It means the same as in human efficacy.

8. Page 4 of the RFP states "All Pivotal studies, as defined by the FDA, shall utilize FDP from a validated manufacturing process and shall be initiated only upon the acceptance of plans and protocols by the FDA and the BARDA Contracting Officer". Please clarify that the term 'validated manufacturing process' refers to the completion of three consecutive validation or qualification batches.

A. For clarification of the term “validated manufacturing process”, please refer to the process validation requirements outlined in the November 2008 FDA Guidance for Industry, “Process Validation: General Principle and Practices”. Per this guidance, “Stage 2 – Process Qualification” describes the requirement to confirm the process design by executing a protocol using the commercial manufacturing process to produce performance qualification (PQ) lots. Thus, the manufacturing process is first validated and from this validated process, three consecutive runs are made for the purpose of demonstrating process consistency (consistency runs). The best strategy is to propose your plan to FDA first.

9. In the first paragraph of pg. 4, the solicitation states “The Contractors shall obtain information from the FDA regarding data needed to support use of the Contractor’s product prior to licensure under a declared emergency.” When should the Contractor assume that the overall regulatory plan will generate data meaningful to this assessment. Should the Contractor plan to submit some form of regulatory package with the express objective of requesting EUA consideration?

A. No, the Contractor should plan on following input from the FDA. Although, licensure is NOT required within the base 5 year term of the contract, the phrase in the RFP was worded to emphasize BARDA’s overall/ultimate objective for a licensed product for the SNS – so that the plans proposed under this final RFP will clearly move the proposed therapeutics towards that objective.

10. The last sentence of the first paragraph of section (c) on pg 4 suggests that the list of studies outlined must be included in any proposal and that addition or deletions must be approved by the Contracting Officer. Is this stipulation meant to apply only after contract award?

A. Yes, any deviations from the final RFP or accepted proposal during performance must be approved by the CO. This is a contract performance requirement accounting for information acquired from completed trials may influence the need for future trials.

11. On pg 11 Paragraph 6 suggests that study protocols will need to be submitted for all clinical trials. Does this obligation apply to non-clinical efficacy studies as well?

A. Yes. Pre-clinical safety and efficacy designs should be reviewed by BARDA prior to their execution.

12. The timeline for submission of final study reports to BARDA is too short. Additional time to synthesize and report key findings is needed.

A. The final RFP was modified to require the final study reports within 30 days of study analysis completion; comments from CO within 30 days; final report within 30 days after receipt of CO comments.

13. The RFP Task 2 mentions a "Project Management Program that meets all HHS reporting requirements": Please define HHS reporting requirements. Are there published references or other sources that list the requirements?

A. The HHS reporting requirements are outlined in the deliverables (section F). This section of the Final RFP has was also modified to clarify requirement.

14. The RFP Task 4 (page 5) refers to mapping the manufacturing process using a WBS to the task level; Section L Part 2 (page 36) mentions a program level IMS that rolls up all time-phased WBS elements down to the activity level: Do "task" and "activity" both refer to the same level that represents the lowest element (terminal element) in the WBS?

A. The terms task and activity are interchangeable and have the same meaning for the purpose of describing the level of detail in a WBS. However, the Final RFP was modified for consistency.

If not, please confirm that only the manufacturing process should reach the lowest element in the WBS. Would the Contracting Office provide a definition scheme for the coding of WBS levels?

A. Task / Activity – lowest element in the work breakdown structure, having no subtasks

Work Package – a group of tasks /activities at the lowest level of each branch of the WBS, includes a MS (deliverable or work package component) for completion

Control Account – the management control point where cost, schedule and performance (MS achievements) are integrated, a collection of work packages (possibly to more then one level below dependant on level of detail, contractor defined, negotiated with USG)

15. Please explain in more detail the concepts of the Integrated Master Schedule and its operation in concert with the Work Breakdown Structure.

A. The IMS contains the Master schedule, which is the top-level schedule that contains contractual as well as program tasks, milestones and activities. It identifies the dependencies in the project plan and integrates the budget, schedule and performance (MS achievement) is reported at the work package and control account levels. Refer to document DI-MGMT-81650 for additional guidance.

16. Please provide additional guidance on the design and content to be included in any risk matrix.

A. The method used for developing and presenting the risk matrix is a business decision of the offeror and they should follow their existing standard operating practices in determining and measuring risks. BARDA will review the information provided for completeness, clarity, and potential program impacts.

17. Stability. On page 5 [task 3 (b) 3] there is a requirement to demonstrate 5 year stability of FDP. On page 43, Evaluation point 3c states the shelf life requirement as longer than 4 years. Please provide guidance on what the minimum required FDP shelf life should be and also what is required to be demonstrated prior to the end of the contract period. As per earlier RFP, would a 3 year shelf life be acceptable? Typical shelf life for most approved biologics is in the range of 2-3 years.

A. The Final RFP was changed to read “Expiration Dating - Stability test results shall support an FDP dating period of at least three years. In addition, Contractor shall, within six months of the contract initiation, create a program to pursue at least a five year expiry.”

18. Also on page 5 task 3(b)3 the RFP states "Contractor shall, within six months of the contract initiation, create a program to pursue at least a five year expiry". Please clarify if this refers to the initiation of stability program or formulation optimization activities to support the objective of a 5 year shelf life.

A. This refers to initiation of a stability program.

19. Is it acceptable that activities initiated to achieve a product stability period of 5 years are likely to extend beyond the end of the contract period of 5 years?

A. The performance period for this contract is limited to 5 years maximum. However, it is possible that a follow on effort of successful candidates is awarded which may include the continuation of an ongoing stability period.

20. The final scale required for the manufacturing process is dictated by the number treatment courses that will need to be provided over a defined period. Please provide guidance on the required treatment courses and the time span for delivery.

A. This solicitation will not procure treatment courses for the SNS. The potential exists for successful candidates to receive a follow on competitive award for the procurement of treatment courses for Neutropenia for the SNS. This guidance is being defined based on threat assessments and is not available at this time.

21. Will past performance evaluations / questionnaires need to be submitted in support of the past performance information?

A. Past performance evaluations are a required submission as part of the past performance volume. See Volume II in section L.

22. How many contracts / experiences should be documented for BARDA?

A. No minimum or maximum although they need to fit the parameters for submission, current within 3 years, relevant and within the page limitations.

23. The requirement for monthly submission of the FMR (as an invoice) seems to suggest that payments will also be made monthly. Is this an accurate assessment?

A. Yes

24. Is obtaining certified cost and pricing data sign-offs not a requirement for 09-33?

A. Certified cost and pricing data is required and stated in Volume III (1) of section L. The certificate may be found in FAR 15.406-2.

25. The operation of HHSAR 352.232-75 Incremental Funding seems to limit the funding for 09-33 to an annual basis. This will create significant project and subcontractor management challenges for a contract of this complexity. Is this requirement necessary? If so, what lead times will the contractor have to initiate work packages that would extend beyond the currently funded period?

A. The HHSAR clause is required unless fully funding at time of award which is not expected. FAR Clause 52.232-22 Limitation of Funds requires the contractor to notify the Government when they have reached 75%, or know they will reach 75% within the next 60 days, of funds obligated.

26. Are there guidelines for developing a project plan than breaks activities into < 12 month activities in anticipation of annual funding decisions? This would be helpful for the Offeror and subcontractors in considering how best to respond to the 09-33 solicitation and project plan requirements?

A. As a recommendation, the project plan may be laid out to efficiently meet the program goals over the life of the contract and then split the plan into 12 month increments as best possible.

27. Section K, point #2 at the top of pg 23 states “Complete this Section and include it part of the PRICE/COST PROPOSAL.” What is the intention of this instruction? Is it simply to include the details that would be included for the underlined sections?

A. The purpose of the instruction is to notify potential offeror’s of the requirement to submit the appropriate representations and certifications. Failure to do so will result in an offeror being determined non-responsive and their proposal rejected. The statement addresses required certifications that are not covered under the Online Representations and Certifications Application (ORCA). The RFP was modified to clarify the statement.

28. (a) Please confirm that a single offeror with more than one potentially viable technical approach to the RFP's requirements, e.g., two therapeutic molecules, may submit multiple proposals in response to the RFP, so long as each proposal individually meets the requirements of the RFP?

A. Yes, each proposal will be evaluated as a stand-alone effort.

(b) If yes, would the “second proposal” have the same page limitations as the “first proposal” (specified on page 33 of the RFP)?

A. Yes.

(c) If no, would BARDA be willing to allow additional pages in an offeror’s Technical Volume and Price/Cost Volume over the page limitations listed on page 33 of the RFP? If not, please advise as to how page count issues would be resolved given that a proposal offering multiple technical solutions, e.g., two therapeutic molecules, would have to provide separate clinical, non-clinical and manufacturing plans, and thus the proposal would likely be substantially longer.

A. Not Applicable.

(d) Would it be permissible for an offeror to cross-reference common sections of its multiple proposals?

A. No – each proposal must be stand alone.

29. BARDA’s digital upload system has proven to be extremely convenient and reliable when we have used it in the past, and there is no question that it is environmentally friendly. We believe allowance of electronic submissions by upload to be extremely desirable. Would BARDA consider permitting proposal submission in this manner?

A. No, Submission of proposals must be done in accordance with the solicitation which does not permit electronic submissions.

30. (a) Does “manufacturing scale-up supporting consistent lot-to-lot manufacturing” in Section C.2 (Scope of Work) (page 3) mean support of development of a commercial scale process capable of delivering sufficient quantities into the SNS under a future acquisition?

A. Yes.

(b) If so, can BARDA please clarify reasonable ranges of terms of that future acquisition e.g., timeline and number of treatment courses, so that an appropriate level of scale-up may be proposed?

A. This solicitation will not procure treatment courses for the SNS. The potential exists for successful candidates to receive a follow on competitive award for the procurement of treatment courses for Neutropenia to be placed in the SNS.

31. Please confirm that support of development of animal models (Section C.2, bullet 3) will extend, if necessary, to screening of potential animal models in order to pick the right one to develop.

A. Yes.

32. In Section C.3, Description of Tasks, beginning on page 3, there are 5 main Tasks listed, with stability encompassed by the Product Suitability task, and manufacturing separate from security, while facilities is not listed. On page 34, however, Volume I is described as requiring a presentation of “the four aspects of the Statement of Work,” with Product Stability replacing Product Suitability, and Manufacturing, Facilities and Security lumped together as a single “aspect.” Furthermore, Section C.2 (Scope of Work) lists 4 bullets describing ARS product development activities that are also not consistent with the more specific 5 Tasks described in Section C.3. As the structure of RFP responses will be dictated by the Tasks and the description of the SOW, can BARDA please clarify this nomenclature and organization?

A. Updated Final RFP to harmonize language.

33. We perceive a disconnect in the draft RFP, in that it suggests that Contractor’s product could be used in an emergency prior to licensure, requiring consultation with FDA on the pathway for use of the product in such an emergency, while at the same time the government states that “the goal of HHS is to have licensed/approved countermeasures in the SNS.” (Section L.6.8, Part 1, paragraph (a) (page 35)). Furthermore, phrases that suggest Offerors provide plans that “support initiation and/or continuation of an IND for the ARS indication (without any clinical holds) and subsequent accrual of data that supports eventual FDA approval/licensure” are vague. (Section C.3, Task 1(a) (emphasis added) (page 3))

(a) Can the government outline expectations for the Contractor more clearly in this regard?

A. It is the Governments goal to place licensed/approved products into the SNS. Companies have the responsibility to understand, at a very early stage of development, the proposed path to licensure/approval for their product for the proposed indication. The Government also has the option to pay for and place products in the SNS pre-licensure/approval based on the sponsor fulfilling a data set sufficient to support the potential use of the product during a declared emergency under an EUA. The sponsor has the responsibility to understand the data set that would be necessary to support the use of the products. The data to support the use of the products during a declared emergency should be data that could also potentially support licensure/approval of the product.

(b) Is the objective of the government for the Offeror to have completed all studies in Section C.3, Task 1(a) and (c) in the 5 year performance period even if all Tasks are not required to meet the government’s goals? Can the government outline expectations for the Contractor more clearly in this regard?

A. Not necessarily. The list of studies (which will be negotiated with the prospective awardee(s)) will depend on the TRL of the proposed therapeutic. The Offeror has an opportunity to propose alternative studies with rationale and the Contractor may deviate during performance with justification and approval.

(c) Alternatively, is the objective of the government for the Offeror to provide, regardless of whether all studies in Section C.3, Task 1(a) and (c) have been completed, sufficient data filed to the IND to allow the FDA to assess if the product may be used in such an emergency under an EUA or alternative regulatory pathways such as a “Contingency-Use IND”? Can the government outline expectations for the Contractor more clearly in this regard?

A. The goal of BARDA is to have the contractor move to a license as soon as possible. All other contingencies are in fact contingencies and should not be viewed as contract goals.

34. In Sections C.3, Task 1(c) (page 4) and L.6.8, Part 1, paragraph (c) (page 35), the draft RFP refers to Phase 1, Phase 1B, Phase 2A and Phase 3 studies; however, (at least for this Offeror) FDA only requires safety studies in normal healthy subjects rather than any specific patient population. Can BARDA please confirm that the contractor is only obligated to perform studies at specific Phase levels as required by the FDA notwithstanding the nomenclature used in the RFP?

A. Yes, the Offeror can modify the list in the RFP and provide justification. FDA guidance on appropriate studies could certainly be included as justification. During the period of performance, FDA guidance should be considered throughout to determine the appropriate path to licensure.

35. Section C.3, Task 1(a) on page 3 states that initiation or continuation of an IND for the ARS indication will be “without any clinical holds.”

(a) Does this mean that there are no clinical holds at the time of proposal submission or that there are no clinical holds at any point in the clinical development program moving forward?

A. At time of submission

(b) If it is the latter, what does occurrence of a “clinical hold” at any point during the contract mean? Will the contractor be given an extension? Could the contractor be penalized for the occurrence of a clinical hold?

A. N/A

36. According to Section C.3, Task 1(a) (page 3), integrated clinical, non-clinical and regulatory management plans must support accrual of data for eventual FDA approval for the ARS indication. Can BARDA please confirm that licensure is not required within the base 5 year term of the contract? Such a construction would be inconsistent with the government’s statement in Section C.2 (page 3), “Ultimately, under a separate acquisition, it is the goal of BARDA to acquire a Final Drug Product that is licensed for the ARS indication.”

A. Yes – licensure is NOT required within the base 5 year term of the contract, the phrase in the RFP was worded to emphasize BARDA’s overall/ultimate objective for a licensed product for the SNS – so that the plans proposed under this RFP will clearly move the proposed therapeutics towards that objective.

37. Section C.3, Task 1(b) (pages 3-4) states, “The regulatory requirements for FDA approval/licensure are likely to be defined in an iterative decision-making process with the appropriate CDER/CBER authorities, based upon the ongoing review of the product during the advanced development process and as specific product-related data emerge.” While the list of non-clinical and clinical studies that will be included in the proposal will be significant and consistent with that outlined in the draft RFP, the development pathway is likely to present additional FDA requirements based on the iterative process outlined in the draft RFP.

(a) How does the government envision funding additional studies that are subsequently determined as necessary for EUA/contingency use and BLA/NDA approval?

A. Required changes that are in scope of the award, such as this example would be, will be added through negotiated modifications?

(b) Should the Offeror propose additional studies that could be required during the pathway in the proposal or wait until these studies are demonstrated to be required?

A. The Offeror should propose what is believed to be the right path to achieve the stated requirement. Additions or deletions to the studies list may be proposed with appropriate rationale. The Offeror should not propose additional studies that are beyond the Offeror’s best estimate of what will be required.

38. The draft RFP states in Section C.3, Task 1(c) (page 4), “Continuation of effort on initial and subsequent studies and associated funding will be based on contractor performance, timeliness and quality of deliverables, and consultations between the Contractor and HHS.” Please provide clarification concerning the parameters and weighting of contractor performance, timeliness and quality of deliverables. What standards will be used to determine whether the continued effort of a contractor will justify the associated funding?

A. Standard Contractor performance categories as documented on the SF294/SF295 and eSRS (see section F.5/F.6): Quality, Timeliness, Price/Cost and Other as may be necessary for unusual items. The baseline for performance will be the accepted IMS and Initial Baseline Financial Report.

39. Will BARDA commit to responding to submitted plans/protocols within a fixed time-frame so that an awardee can maintain its proposed schedule, coordinate with its subcontractors (Section C.3, Task 1(c)) and can plan how many days, for example, the COTR will need to review and approve of plans/protocols prior to submission to the FDA?

A. It is the intent of the USG to respond within two weeks of receipt. The higher the quality of submission submitted by the sponsor the shorter the review time required.

40. Given the uncertain nature of an ARS clinical setting, the purpose of non-clinical studies designed to match the clinical age-sex equivalents in the non-clinical program is unclear (Section C.3, Task 1(c) on page 4). Additionally, only non-clinical efficacy studies (and not toxicology) are required to match the age-sex equivalents of the clinical setting. Would BARDA consider removing this requirement, especially given the issues associated with acquisition of female NHP in significant quantities (e.g., non-availability)?

A. The populating of the NHP pivotal Animal Rule studies is a negotiation of the Offeror with the FDA and is not a BARDA requirement. The requirements for age-sex weighting to the pivotal efficacy studies is a rationale part of pivotal GCP trials and the FDA, as they stipulate in the Animal Rule, wish all pivotal studies to be designed as surrogate trials for the human Phase 3 trials for defense of the labeling. BARDA has this described in Section C.3. Task 1(c) for the Offeror to prepare a rationale for the exemption or final design of the trials and with the desire that the rationale is prepared under the advisement of the FDA.

41. With respect to Section C.3, Task 1(c), Non-clinical #1 and #11 (page 4) and Section L.6.8, Part 1, paragraph (b), Non-clinical Studies #1 and 11 (page 35):

(a) Are these intended to be natural history studies at a single radiation dose level?

A. No. Single radiation dose levels are not supportive of licensure. It is the purpose of the Final RFP to define the product safety and efficacy parameters over expected radiation burdens and pathogenic time frames. The goal of the RDFP is to foster development of a product along an anticipated regulatory path toward eventual licensure for the an indication as a medical countermeasure for neutropenia arising from ionizing radiation exposure.

(b) Why was only the single LD chosen?

A. A single LD level was written as an example. It is the intention of any CRN advanced development to show performance of a medical countermeasure with respect to radiation (or chemical) dose, countermeasure dose, countermeasure formulation (PK and PD relationship),

42. It appears that Non-clinical #2 and #3 in Section C.3, Task 1(c) on page 4 (see also Section L.6.8, Part 1, paragraph (b), Non-clinical Studies #2 and #3 on page 35) can be combined and the rationale behind a single dose PK study in irradiated animals is unclear.

(a) Will the government accept proposals that minimize duplication of activities between studies?

A. Yes. However, some duplication across studies is useful and may be required to bridge information.

(b) If the government will accept such proposals, will a proposal be downgraded for combining the two studies?

A. The government will accept such proposals and there will not be any downgrading of proposals for combining studies unless a combined study is not in the best interest of the information to be gathered or introduces confusion on interpretation of results.

43. Section C.3, Task 1(c), Non-clinical #2, #3 and #8 on page 4 (see also Section L.6.8, Part 1, paragraph (b), Non-Clinical Studies #2, #3 and #8 on page 35), refers to Irradiation (IR) at 6 Gy.

(a) Does the government have a specific expectation of radiation source - LINAC, Co-60 or AFRRI?

A. No. The stipulation is simply exposure to ionizing radiation (x-ray or gamma ray are acceptable; exposure to alpha or beta radiation sources will not have the anticipated depth dose distribution which we wish to achieve. Dosimetry of the subjects should be through a validated process and descriptions of the source, depth dose distribution and coefficient of variation across the irradiation fields are expected. There is a minimum dose rate anticipated and that is >20 cGy/min.

(b) Can the government provide a rationale for the 6Gy given for studies #2, #3 & #8?

A. 6 Gy is commonly referred to as the human lethal dose for 50%. It is not intended to be a “hallmark” for all studies and represents only a benchmark for defining the anticipated work plan.

44. Under the previous RFP, pediatric and geriatric studies were to be conducted post-licensure. However, Sections C.3, Task 1(c), Clinical # 5 and # 6 (page 4) and L.6.8, Part 1, paragraph (c), Clinical studies # 5 and #6 (page 35) of the draft RFP require such studies to be performed within the proposed 5 year performance period, which may be difficult due to significant recruitment challenges in these subject populations (especially pediatric subjects) and the inability to define the clinical dose for use in these studies until at or near the end of the program.

(a) Please confirm that BARDA is requiring these studies within the first five years, regardless of whether the FDA has requested these studies to date.

A. Not necessarily, the Offeror can modify the list in the RFP and provide justification.

(b) Would BARDA be willing to consider extending the term of the contract to accommodate the completion of these studies or to make these separate contract line item options in the event that BARDA or FDA requires these studies during the five year period?

A. The possibility exists with in the Federal acquisition laws to permit a short extension depending on the probability of completion. This consideration will be given near the end of the contract period based on the situation.

45. Please confirm that the NHP-14 day repeat dose + 6 Gy study in Sections C.3, Task 1(c), Non-clinical #8 (page 4) and Section L.6.8, Part 1, paragraph (b), Non-clinical Studies #8 (page 35) is a toxicology study in irradiated animals rather than an additional efficacy study.

A. All studies listed are intended to be vetted for each medical countermeasure that applies for the RFP. In some cases a study may be unnecessary or inappropriate. The listings are NOT intended to be a “complete all and receive approval” menu. They are to be designed with your product in mind and vetted in discussions with the regulatory authorities. Toxicology studies in irradiated animals may be a consideration if under the resultant effects of radiation the medical countermeasure may exhibit deleterious effects not seen in normal subjects.

46. In the non-clinical program (Section L.6.8 Part 1, paragraph (b), Non-clinical Studies #9 on page 35), the government describes drug-drug interaction studies involving five relevant drugs; however, in section C.3 it mentions “several” drugs (Section C.3, Task 1(c), Non-Clinical #9 on page 4).

(a) Can the offeror define several drugs (i.e., 3-5) that are most clinically relevant, as permitted by Section C.3, instead of the 5 required by Section L.6.8 Part 1?

A. Treatment of radiation exposed victims can involve a wide variety of therapeutics. The selection of a drug for a drug-drug (D-D) interaction study should be vetted across the time frame of use of the product, co-injection possibilities, product interference, either competitively or non-competitively, with a required receptor or tissue functionality. The choice of any drug(s) for study is based upon known issues (ADME, immuno-functionality, clinical artifact or assay interferences, etc) of the countermeasure you are proposing.

(b) Does the government have a specific list of medications that have been identified?

A. You can refer to the REMM site (www.remm.nlm.gov) for examples, but the MCM you are proposing may have unique drug-drug (D-D) activity that the Offeror should reveal.

(c) Would the government consider acceptance of clinical drug-drug interaction if these are considered feasible and ethical rather than non-clinical drug-drug interaction studies?

A. Known clinical D-D interactions of a licensed product are important and should be the first line of studies; however, radiation induced injury may create specific new issues and drug combinations that should be considered beyond the current licensed clinical application.

47. If a specific study, such as the NHP Neutrophil function in Sections C.3, Task 1(c), Non-clinical #18 (page 4) and Section L.6.8, Part 1, paragraph (b), Non-clinical Studies #18 (page 35) is embedded or studied in other NHP pharmacokinetics/ pharmacodynamics or efficacy studies, would this meet the government’s expectations? If such a combination of studies is acceptable to the government, will a proposal be downgraded for combining the studies?

A. Yes, the USG will accept merged studies providing the study is not confounded by such merges and the data is reasonably interpretable. There should be no downgrading of a proposal for such designs unless they are viewed as confusing to the outcomes.

48. With regard to audits of subcontractors required by Section C.3, Task 1(e), on page 5, must the contractor be able to make subcontractor records and staff available for other than normal business hours? If so, how much notification will be provided in order to plan an after-hours audit?

A. The Government will not conduct “other than normal hour audits” as a result of normal procedures.

49. Section C.3, Task 2(c) on page 5 states that the contractor shall use subcontractors “at their discretion” for activities involved in research and product development.

(a) Please confirm that, based on this statement, subcontractors and subcontracts do not require HHS approval?

A. Use and selection of subcontractors is at the sole discretion of the Offeror in the building of a teaming arrangement. HHS approval is not required as vetting of subcontractor capability will be accomplished in the evaluation process.

(b) Please confirm that there is no restriction on the use of subcontractors with respect to the scope of work.

A. There is no restriction except those required by statute, regulation and policy.

50. In Section C.3, Task 3(a) (page 5), can BARDA please confirm that submission of “data and evidence to demonstrate suitability of the proposed product for potential use in a declared emergency in treating neutropenia resulting from ARS” represents an objective of the contract rather than a prerequisite for consideration, i.e., an offeror will not be excluded from consideration for award?

A. Yes.

51. (a) Section C.3, Task 3(b)3 (page 5) requires results supporting 5 year stability and also requires establishment of a program to pursue a 5 year expiry. Please clarify the intended distinction between stability and expiry.

(b) Additionally, paragraph (c) of Section M.1(3)b, Evaluation Point 3 (Product Suitability) (page 43), states that “products which have a shelf life longer than 4 years” will be viewed more favorably. We note that this, along with the 5 year stability or expiry period in Section C.3, Task 3(b)3 (page 5), is a significant change from the previous RFP (HHS-BARDA-08-10), which required 36 months, with 30 months remaining at delivery to the SNS. Please explain if this significant change was intentional.

(c) Is paragraph (c) of Evaluation Point 3 inconsistent with Section C.3, Task 3(b)3 (page 5)?

A. During the period of performance, the awardee will initiate a 5 yr stability/expiry study/program. For proposal evaluation, any existing stability data should be provided. Proposed products that are stable for 3 or more yrs will receive more points.

(d) Is it acceptable to submit a proposal with less than 5 years stability test results with a commitment to complete studies to support 5 years?

A. Yes.

(e) If the answer to question 3(d) is yes, is there a lower limit on current stability test results required, 4 years or otherwise?

A. RFP changed to say at 3 years for additional points.

52. With regard to the Manufacturing plan required under Section C.3, Task 4(a) (page 5), could BARDA please provide more specific guidance as to what is meant by “fully mapped using a Work Breakdown Structure to the task level”?

A. The term “fully mapped using a Work Breakdown Structure to the task level” describes the project management requirement for mapping the manufacturing process to identify steps to the task level. This project management tool shall assist in identifying key and linked tasks.

53. (a) Paragraphs (b) and (c) under Section C.3, Task 4 (page 5) appear to require that the offeror be actively manufacturing the product and that an ongoing capability to manufacture must be demonstrated through an implemented plan which will be verified by both BARDA and FDA audits during the entire period of performance. Is this a correct interpretation?

A. Paragraphs (b) and (c) under Section C.3, Task 4 (page 5) refer to the manufacture of material during the performance period of this contract. The product shall be manufactured in accordance with cGMPs and used as described in this solicitation, in activities including, but not limited to, non-clinical and clinical studies, process characterization studies, process validation studies, stability studies, etc. Site visits to verify compliance with cGMPs shall be facilitated by the contractor.

(b) In order for Offerors to provide the best value, can the government please define the minimum “ongoing capability” for manufacturing that would be acceptable during “warm base” periods when product is not actually needed for the development program?

A. The “ongoing requirement” is product and company specific and varies based on situational and programmatic considerations.

54. Can BARDA please advise how many meetings per year in Washington, DC, are anticipated, and what staff will be required to attend? (See Section C.4 on page 6) A. One meeting per year is anticipated and relevant program staff should attend.

55. With regard to Section F.5 Deliverables, deliverable #1 (Initial Baseline Financial Management Report) (pages 9-10 and 12), we believe that the requirement to provide the entire 60 month baseline within 30 days of award is neither possible nor necessary, because of various changing deadlines and variables.

(a) Would BARDA consider permitting submission of this report on a month-by-month basis for the first 12 months of contract performance, and annually thereafter?

A. The baseline financial report is what the Contractor estimates to be the expenditure rate based on their proposed plan. The data is readily available as part of the business process in formulating the technical and cost proposal for the entire contract period. The 30 days is an allowance for any modifications that may be required as a result of negotiations just prior to award. Failing to have these data would raise serious concerns about the validity of the plan and estimated costs.

(b) Furthermore, how much time will contractors be allowed in order to revise the baseline financial report after each change?

A. Subject to instructions given at time of change but no more than 30 days.

56. Section F.5 Deliverables, deliverable #1 (Initial Baseline Financial Management Report) (page 9) states in the second paragraph, “The total estimated cost and direct labor hours reflected in the baseline report must equal the contract values for the total contract period.” However, this excludes other values that are properly included in the values for the total contract period, e.g., fee and general and administrative costs. In fact, other values are included in the next paragraph, which lists 10 minimum reporting categories. Can BARDA explain this inconsistency?

A. The total estimated cost is an aggregate of the minimum reporting categories or individual cost elements. This total value must also equal the proposed estimated price for the contract (contract value). Similarly, the total estimated direct labor hours must equal the number inserted on this form. This is not an inconsistency, it is a consistency check between what the negotiated contract value and the total of all estimated cost elements.

57. (a) With regard to F.5 Deliverables, deliverable #1, (Initial Baseline Financial Management Report), Attachment 1, Instructions for #9, please clarify what is meant by the statement “for each sub-division of work”?

A. Sub-divisions refer to stand alone divisions of work that are required for completion and that correlated cost schedule activity is not required. As a cost reimbursement contract, correlated cost schedule activity is required for all work and this instruction does not apply for this effort (b) F.5 Deliverables, deliverable #1 lists minimum reporting categories including, for example, Direct Labor Hours and Direct Labor Dollars. Can BARDA provide guidance as to how both the minimum reporting categories and the sub-divisions required by Attachment 1, Instructions for #9 be indicated on this form? If reporting is to be by the minimum reporting categories, will the estimated completion date for the contract line item be the same for all lines?

A. Subdivisions are addressed above. Report direct labor hours as estimated for performance of the effort. Report direct labor dollars as a multiple of wage rate times estimated hours. Report all other minimum categories per the approved indirect cost allowances related to the direct cost pool and cost of material, travel, etc. The estimated completion date would be the date when work is expected to be completed per CLIN and is inclusive of all minimum reporting categories

58. (a) With regard to F.5 Deliverables, deliverable #1, Attachment 1, Baseline Financial Management Report, can BARDA please provide clarification as to what is required in the “Scope of Work” in box 1.c, and specifically how this differs from Contract Line Item Number (CLIN) 0001, which constitutes the entire work to be performed. Will the contractor be required to report on forms under Attachment 1 and Attachment 2 for anything other than total contract line item?

A. The “Scope of work” on this form is a short title of the effort. In this case, something to the affect of “ARS Nuetropenia Indication” would work. It is simply a short title/description of the effort that the report relates too. The scope of work and contract line item number have no relation in practice. Although they may read the same, the scope of work is the “title” and the CLIN is the work being performed. The Contractor will be required to report the total contract line item costs for each period by individual cost element.

(b) If multiple forms are required based on a specific breakdown of the work to be performed under CLIN 0001, can BARDA please provide guidance as to what the appropriate subdivisions of CLIN 0001 are for this purpose?

A. The form allows for a breakdown of estimated costs by month. There are a total of 12 months on the form. Multiple forms must be filled out in chronological order from month #1 through month #n. This may vary for each Contractor depending on the final estimated timeline and schedule. Note that this report is not required until 30 days after award.

59. With regard to Section F.5 Deliverables, deliverable #2 (Monthly Financial Management Report) (pages 10 and 12), Offeror believes 10 working days to be insufficient because information must be obtained from subcontractors. Would BARDA consider providing additional time for monthly FMR submission?

A. The MFMR provides two key data elements. First it is an indication of how performance is going in relation to the baseline estimate at the onset of performance. Second, it serves as the Contractor’s invoice for payment. Under a cost reimbursement contract, accurate and timely reporting of accrued costs is required. This includes that of subcontractors. The prime must have accrual and tracking systems in place to provide accurate financial data. Ten working days following the close of the Contractor’s reporting period is not extendable.

60. Does the submission of a monthly Financial Management Report required by Section F.5, deliverable #2 (pages 10 and 12), guarantee monthly payment?

A. The payment process will be commensurate with standard invoice processes. The MFMR/invoices will be reviewed and once approved, sent to distribution for payment. Normally this is anticipated to happen within the 30 day cycle.

61. Section F.5 Deliverables, deliverable #2 (Monthly Financial Management Report) (pages 10 and 12), requires narrative explanations for variances exceeding +/-5%. We believe that a higher threshold would be more reasonable without negatively affecting the government’s interests (we understand that industry standard is +/-10%).

(a) Would BARDA consider raising this threshold?

A. No. The threshold is established as a management tool and the variance requiring a narrative explanation will remain at +/- 5% based on the monthly estimated cost. At this frequency and level, the narrative is generally very short.

(b) Will the variance explanation be required for variances that exceed the threshold by reporting category, scope of work, contract line item, or some other basis?

A. The variance is based on the total estimated cost to date (initial baseline report) compared with the actual cost to date for any given time period. It is an aggregate of all categories, line items, etc. All cost categories will remain proportional to direct labor charges with the exception of material, travel and potentially subcontractor/consultant costs.

62. RFP Section F.5 Deliverables, deliverable #3 (Final Security Plan) (page 10) states that the contractor shall provide a "letter certifying compliance" with the approved Final Security Plan. Is this requirement simply a letter certifying that the contractor has implemented all material aspects of the security plan included in its proposal to BARDA? If not, please clarify what this letter should include.

A. The letter will serve to certify that the Contractor understands the security requirements and will operate within those requirements. Security requirements may be a topic of negotiation due to variables that exist or alternative measures that may be proposed. The Security Plan does will not effect scoring of proposals but must be acceptable prior to receiving an award.

63. With regard to Section F.5 Deliverables, deliverable #5 (Annual Technical Progress Reports) (pages 11-12), we believe that requiring the report within 15 days after the contract anniversary date is extremely ambitious, and maybe not possible. Would BARDA consider extending this deadline?

A. No-the annual report is a summary of the year’s performance which has been reported monthly in the monthly technical reports with the inclusion of the 12th month’s report. Essentially, 11/12ths of the annual report can be completed prior to the end of the anniversary period. Fifteen days should be sufficient.

64. Non-clinical and clinical studies report (draft, comments and final report) timelines are very stringent (Section F.5 Deliverables, deliverable #7 requires draft reports to BARDA within 15 days of completion of study data analysis, comments from the contracting officer within 30 days, and the final report within 30 days after receipt of the contracting officer’s comments.) These short deadlines will not allow sufficient time for appropriate review of the report prior to submission to the government, especially the 15 days for first draft report.

(a) Would BARDA consider modifying the deadline for the draft report to within 30 working days?

A. The Final RFP was modified to 30 days for the draft report.

(b) Can BARDA please confirm that confirmation of “completion of analysis of data,” which starts the timeline for submitting a draft report, will be determined by Contractor?

A. Yes.

65. With respect to Section F.5 Deliverables, deliverable #7 (page 11), Final Study Reports, can BARDA please confirm that only clinical study reports (not non-clinical study reports) must follow ICH E3? This guidance document only refers to clinical trials.

A. The Final RFP wording has been changed to require only clinical trials follow ICH E3.

66. The RFP states that FDA submissions must only be provided to BARDA personnel within 30 days of being submitted to FDA (F.5, deliverable #8 (pages 11-12)).

(a) Does BARDA require review of all regulatory submissions (other than study protocols) prior to submission to FDA?

A. Yes

(b) If so, what time frame should the contractor build into the Gantt chart for this review?

A. It is the intent of the USG to respond within two weeks of receipt.

67. With regard to Section F.5 Deliverables, deliverable #11 (Audit Reports) (pages 11-12), can BARDA please elaborate as to the full scope of interim and final audit reports being considered, and which reports Contractor will be obliged to supply?

A. The Contractor is obligated to submit all audit reports produced related to the performance of this effort. “Interim” audit reports refer to those audits performed from the onset of performance that may have a reoccurrence throughout the life of the contract. “Final” audit reports refer to the last audit performed related to this contract. Note, the final audit and/or report may occur after completion of the period of performance.

68. Section F.5 Deliverables, deliverable # 12 (pages 11-12) refers to several “capital-P” “Plans” that are not mentioned as such elsewhere, such as Disposition Plan, Assay Validation Plan and Labeling Plan. Please provide a definitive list of Plans required in the Proposal or clarify the “plan language” where it occurs in the RFP.

A. The Final RFP was modified to clarify.

69. In the chart in Section F.6 on page 12, with respect to lines 9 and 10, is it correct to assume K requires…