B08-HT942726RE009-RPP-Amend0001-Attach1-Questions-Answers-from-Potential-Performers.pdf

Question Answer

I see that the RPP for Battlefield Pain Management – Analgesic has been issued. Is Wearable Pain Blocker prototype device of interest to the RPP? I ask because it is non-pharmaceutical. The WPB uses magnetic coils to noninvasively transmit analgesic stimulation which blocks peripheral nerve conduction. When the WPB is worn proximal to a limb injury, pain from that injury will be blocked. The WPB will enable on-demand analgesia, facilitating battlefield pain management and other medical care, and minimizing challenges associated with drugs. Recently, and tested the benchtop prototype in vivo. It demonstrated reliable blocking of the rabbit sciatic nerve. For up to 30 minutes of block (the longest time tested), nerve recovery afterwards was complete, and no damage was observed histologically. This effort started with a and was then funded by , which is about to end. Our next steps include prototype development and optimization, further in vivo testing (scaling to the pig), and pursuit of an Investigational Device Exemption.

The intent of the RPP is to find a single dose analgesic that can be used pre-hospital in austere environments. If the device requires electricity, even rechargeable batteries, that will be a significant barrier to the intended use. The data are promising and the device does seem well suited for use in ambulances, Roles of care 1-4, clinics, medical centers, and other fixed facilities. The RPP was not revised.

Attachment A (Statement of Objectives), Section 9, "Desirable prototype characteristics and performance," item (2), states:

"The product shall be a single dose product with an intramuscular (IM), intranasal (IN), or oral (PO) route of administration."

Additionally, item (11), states: “ The product may use an applicator device (e.g. autoinjector or nasal spray) that may or may not have a predicate device.” It is most common for autoinjectors to deliver subcutaneously.

The purpose, scope, and objectives of both the RPP and the SOO otherwise describe the requirement in route-agnostic terms (a "rapid, single dose/single use" analgesic for moderate to severe acute pain), and the §9 characteristics are framed as desirable characteristics on which evaluation will be based rather than as pass/fail eligibility criteria under RPP Section 2.6.

Question: Will a single-dose product delivered by the subcutaneous (SC) route be considered responsive and eligible for award? If the enumerated routes in §9.2 (IM/IN/PO) are intended as a strict requirement rather than a desired/evaluated characteristic, please confirm. We ask because an SC single-dose presentation can meet the program's core intent — austere, point-of-injury use; rapid, single-use administration; and the moderate-to-severe acute pain indication — and offers a non-opioid profile directly responsive to the physiological-risk characteristics in §9.16.

Yes, a subcutaneous route of administration will be considered responsive and evaluated in accordance with the RPP. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (2) was revised.

Is there any incumbent/recompete or this is a brand-new project? If yes, could you please provide us with their award number or even if the customer bought similar services in the past.

No, there is no incumbent/recompete. This is a brand new project. The RPP was not revised.

Sublingual eligibility develops drugs using its proprietary wafer technology, which is optimised for sublingual delivery. Our strategy is focused on drug repurposing, using approved active compounds and reformulating them into novel sublingual dosage forms.

The SOO states that the product shall have an intramuscular, intranasal, or oral / PO route of administration. Would DHACA consider a single-use sublingual product to fall within the oral / PO route requirement?

Yes, sublingual route of administration will be considered responsive and evaluated in accordance with the RPP. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (2) was revised.

Scope for a distinct product using sublingual platform i is currently performing under a DoD award ( ) for Wafermine, a sublingual racemic ketamine product. If were to propose a different repurposed approved analgesic compound or ketamine combination using the same proprietary sublingual platform, would DHACA consider that to be within the scope of this RPP, provided that the proposed product is distinct from Wafermine which incorporates racemic ketamine as the sole active ingredient?

Yes, the new product would be within scope so long as it is distinct from Wafermine. The RPP was not revised.

FDA 505(b)(2) / repurposing approved drugs Given focus on repurposing approved compounds, would DHACA consider a product candidate that follows a 505(b)(2) pathway, supported by existing data on the approved active ingredient and the additional studies needed for the new sublingual dosage form and acute pain indication?

Yes, a product that follows the 505(b)(2) pathway will be eligible. The RPP was not revised.

HT942726RE009, Amendment 0001 - Battlefield Pain Management – Analgesic Request for Prototype Proposal (RPP) Questions and Answers

U.S. manufacturing The SOO states that the performer shall have large-scale manufacturing capability and the ability to surge production.

has entered into a joint venture with a U.S. company and will acquire a 503B manufacturing facility as part of its strategy to onshore novel, fast dissolving freeze dry solids manufacturing capability in USA.

Must large-scale manufacturing and surge capability exist at proposal submission or award, or may this capability be established and scaled during the 8-year period of performance? If it must already exist, what baseline capacity would DHACA expect us to demonstrate, including for clinical supply, EUA supply, and potential follow-on production after FDA approval? Or can this requirement be satisfied through a phased manufacturing scale up plan, including using our own facilities, joint venture partners, subcontractors or other qualified manufacturing partners?

Large-scale manufacturing should be available within one to two years of market release so scaling during the period of performance is acceptable. A phased manufacturing plan is also acceptable using personal facilities, manufacturing partners, etc. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (6) was revised.

DEA scheduling clarification Can DHACA clarify what DEA classification is required or acceptable for the proposed product? In particular, does “Schedule II or higher” mean Schedule II or more restrictive, or does it include Schedule III, Schedule IV, Schedule V, or DEA-uncontrolled products?

"Schedule II or higher" means Schedule II, III, IV, V, or unscheduled products. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (13) was revised.

Cost proposal / payment structure i existing DoD award for Wafermine uses a hybrid payment structure, with fixed-price labour and cost-reimbursable elements. For this RPP, may propose a similar hybrid structure, particularly for FDA-dependent workstreams?

Yes, a similar hybrid structure may be proposed. Please see RPP, Amendment 0001, section 2.1 Award Type for additional information. The RPP was not revised.

Attachment A (Statement of Objectives), Section 9, "Desirable prototype characteristics and performance," contains two items addressing controlled-substance scheduling that appear to be in tension. Item (12) states: "The product may meet Drug Enforcement Administration (DEA) uncontrolled classification criteria." Item (13) states: "The product shall be classified as DEA schedule II or higher." Read together, item (12) permits an uncontrolled product while item (13) appears to require a Schedule II or more-restrictive classification.

The purpose, scope, and objectives of both the RPP and the SOO otherwise describe the requirement in schedule-agnostic terms (a "rapid, single dose/single use" analgesic for moderate to severe acute pain), and the §9 characteristics are framed as desirable characteristics on which evaluation will be based rather than as pass/fail eligibility criteria under RPP Section 2.6.

Item (9) separately requires only that the performer meet the statutory and regulatory requirements to manufacture, store, and distribute controlled drug substances, which is achievable for any scheduled product.

Question: Will a single-dose product whose active ingredient is a DEA Schedule III controlled substance be considered responsive and eligible for award? If item (13) ("Schedule II or higher") is intended as a strict requirement rather than a desired/evaluated characteristic, and is intended to exclude Schedule III products, please confirm. We ask because a Schedule III analgesic can meet the program's core intent — austere, point-of-injury use; rapid, single-use administration; and the moderate-to-severe acute pain indication — while offering a non-opioid profile directly responsive to the physiological-risk characteristics in §9.16, and is fully compatible with the controlled-substance handling requirements in §9.9.

"Schedule II or higher" means Schedule II, III, IV, V, or unscheduled products. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (13) was revised.

THE ISSUE

A point of clarification, please?

As the Government Knows -- Drug Enforcement Administration schedules run I to V. That is, level or schedule I is most controlled. And level/schedule V is for least controlled. Schedule II is more restricted than Schedule III.

As this program stated, the opioids this program backfills, DSUVIA (sufentanil) and Oral Transmucosal Fentanyl Citrate (fentanyl), are/were Schedule II.

Ketamine, for example, is Schedule III.

This is one step lower in control.

In the presented documentation, Constraint 13 requires the product to be "Schedule II or higher."

A literal reading excludes Schedule III. This would therefore exclude ketamine. I believe that was an error.

Constraint 12 makes the confusion worse by permitting an "uncontrolled" product, the opposite of 13.

The two constraints point in opposite directions, and ketamine sits in the Schedule III gap between them.

MY QUESTION, TO THE GOVERNMENT, PLEASE

Constraints 12 and 13 appear to conflict.

Constraint 13 requires a Drug Enforcement Administration Schedule II or higher, while constraint 12 permits a product that meets uncontrolled criteria.

Please clarify whether a Schedule III product, such as ketamine, satisfies constraint 13, given that leading non-opioid battlefield analgesics are Schedule III.

Is the intent of constraint 13 a minimum control floor rather than a strict exclusion of Schedule III?

Is Ketamine a Schedule III permitted?

1) "Schedule II or higher" means Schedule II, III, IV, V, or unscheduled products. The RPP, Attachment A - Statement of Objectives, Desirable prototype characteristics and performance, (13) was revised.

Constraint 6 requires "large scale manufacturing capability and ability to surge production" but sets no specific numbers.

What "standard or large sxcale" production rate is expected and what "surge" in other words could you please help and define, in this case "large scale" and "surge" for evaluation, in units or doses and over what period?

Large scale and surge production are meant to cover Joint Forces during conflict. Predictions of exact amount are not possible due to the volatility of conflicts. This amount will likely flux as additional analgesics are added to DoW capabilities. As an example, approximately 45,000 vials of ketamine (450,000 doses at 50mg/mL) are required to be stocked at all times.

Production capacity would need at least to maintain the stockpile during conflict and provide surge capacity for unexpected events or missions. The potential length of a surge is unknown, however submitted estimates may be pegged to a historical event such as the Iraq War Troop Surge which lasted approximately 7 months. The RPP was not revised.

Physiological-risk thresholds. Regarding the SOO desirable characteristics in item 16 (≤20% change in blood pressure and heart rate, ≤20% change in coagulation, and minor airway change), will existing clinical safety data be accepted toward demonstrating these thresholds, or does the Government anticipate that dedicated new studies will be required?

Existing clinical data will be considered as demonstrative of the thresholds so long as the clinical data are of a quality and sufficiency to support FDA licensure. The requirement for new studies will be determined by the FDA upon review. The RPP was not revised.

Interim fielding. Given the optional Interim Fielding Capability provision in the draft OTA (Attachment B, Article 1.D.2), will the Government consider an interim or early-delivery mechanism — for example, Expanded Access or a compounded formulation

— during the development program? If so, how should offerors reflect this in the technical approach, and how would it be weighed in the evaluation?

Interim or early delivery mechanisms will be considered as strategies for early delivery. However, the mechanism must be compatible with DoW, DHA, and FDA requirements for use. These mechanisms can be risky with complex approval processes and a significant regulatory/reporting burden. Strategies for early delivery must not prolong the overall FDA approval schedule of the main effort. They will be considered in the evaluation for their feasibility, regulatory/reporting burden, cost, and schedule.

The RPP was not revised.

Weighting of existing data. How will the Government weigh demonstrated prior clinical and pharmacokinetic data against committed new studies in the technical evaluation of the proposed development and regulatory approach?

The Government will evaluate proposals in accordance with the criteria outlined in the RPP Amendment 0001, section 3.3 to include regulatory risk, timeline cost, etc. The RPP was not revised.

Pricing structure. For an eight-year period of performance with no disclosed program budget, may offerors propose a not-to-exceed, milestone-based price structure aligned to the three objectives?

A milestone-based payment structure is encouraged. Most often payments are tied to milestones to attain the objectives versus the objectives themselves. This will allow potential performers to be paid more frequently throughout the process. The RPP was not revised.

Volume II, Spend Plan: The RPP requests a Spend Plan in Volume II (RPP pg. 12), but in the Volume III instructions the RPP states, "...no cost information may be used in Volume I Technical or Volume II Management" (RPP pg. 13). Could the Government please clarify what information should be provided in the Spend Plan if cost information is prohibited from Volume

II?

Vendors shall provide a Spend Plan in accordance with the RPP Amendment 0001, 3.4 Volume II: Management. This information is not prohibited from Volume II. The RPP was not revised.

Volume III, Cost-Support Documentation: The RPP appears to request detailed cost support for subcontractors and sub-performers, including labor categories, labor hours, labor rates, and related cost detail (RPP pg 13, 14). For commercial vendors such as CROs, CDMOs, clinical packaging/labeling vendors, testing laboratories, and nonclinical vendors, this level of labor-level detail may not be available because these vendors often quote work as fixed-price, time-and-materials, or deliverable-based commercial proposals. Please clarify what documentation is required for such commercial vendors.

Specifically, is a vendor quote or proposal that identifies scope of work, deliverables, milestone or task pricing, assumptions, and total cost sufficient, or must each commercial vendor provide detailed labor-hour and labor-rate breakdowns? If detailed labor breakdowns are not available, what alternative cost support will be considered acceptable and compliant?

Vendors shall provide the information required in accordance with the RPP Amendment 0001, 3.5 Volume III: Administrative and Cost Volume. The RPP was not revised.

By what mechanism are grant proposals for this solicitation sent? / Would this proposal be sent through Grants.gov (I don’t see it listed), via email, or some other method/platform?

This is not a grant. This is a Request for Prototype Proposals. The Government's intent is to issue up to two Prototype Other Transaction Authority Agreements. Proposals would be submitted in accordance with the RPP proposal preparation instructions. The RPP was not revised.