Modified_Sample_TORFP_(18-2006).pdf

Attachment 4 (modified 11/27/2017) RFP N01TR-18-2006

Sample Task Order Request for Proposal (TORFP)

A. Task Order Title

Reagent Generation for Bioanalytical Method Development of BIOLOGIC A

B. Task Order Period of Performance

The period of performance for this task order (TO) shall be for twelve months from the time of award.

C. Task Order Type

It is the Government’s preference that this TORFP result in a firm-fixed price TO.

D. Statement of Work

1. Background and Introduction

Hypothyroidism occurs through the stimulation of intestinal uptake of dietary calcium and phosphate. It is most frequently an acquired condition following injury or trauma to the parathyroids, typically following neck surgery. Hypoparathyroidism in childhood is usually associated with congenital conditions which may include a calcium receptor mutation, leading to autosomal dominant hypocalcemia and hypercalciuria, DiGeorge Syndrome, or autoimmune polyglandular failure syndrome type 1. The current estimate for thyroid surgery-associated hypocalcemia at 6 months post-surgery is 4.4%. The Office of Rare Disease Research (ORDR) includes hypoparathyroidism on the list of rare diseases. It has been estimated that approximately 60,000 to 65,000 patients suffer from hypoparathyroidism in the US.

Hypoparathyroidism is conventionally managed with oral supplementation of calcium and calcitirol or other vitamin D analogs. Despite large doses of both medications, many patients still suffer from recurrent episodes of severe hypocalcemia requiring emergency medical attention. Furthermore, long-term adverse effects of conventional therapy include nephrocalcinosis, nephrolithiasis, and impaired renal function.

The goal of this task order is to develop specific anti-BIOLOGIC A antibody reagents for use in bioanalytical assays to measure BIOLOGIC A and antibodies generated in vivo after administration of BIOLOGIC A (including neutralizing antibodies) in nonclinical and clinical studies. For the measurement of BIOLOGIC A, a highly sensitive assay (e.g. low pg levels) is required; therefore, high affinity antibodies are needed. Offeror proposals will be evaluated on the utility of a PTH Receptor Modulator (BIOLOGIC A) that has not only an extended pharmacokinetic profile, but also extended pharmacodynamic interaction with the PTH1 receptor.

2. Scope and Objectives

The scope and objectives of this task order include:

- Develop polyclonal anti-BIOLOGIC A antibodies (ideally with PTH neutralizing activity).

- Develop monoclonal anti-BIOLOGIC A antibodies (ideally at least one with PTH neutralizing activity).

- Characterize the specificity of antibodies.

- Produce purified and modified antibody(s) suitable for assay development.

- Implement and maintain administration and data management systems.

3. Technical Requirements

Upon issuance of a task order, the Contractor shall perform the following activities:

i. Polyclonal anti-BIOLOGIC A Antibody Generation

Animal Models must be hyper-immunized with one or more appropriate immunogens (number of immunogens and immunogenization regimen must be proposed by the offeror and agreed to by NCATS) as required to assure generation of a specific, high titer antibody response. Serial bleeds (low volume test bleeds) must be collected and titered for reactivity with BIOLOGIC A. Once a suitable titer has been achieved, production bleeds can commence. Antisera for anti-PTH antibody assay positive control reagent can be collected from moderate titer bleeds. Antisera for PTH pharmacokinetic assay reagent(s) must be collected from higher titer bleeds to increase chances of producing high affinity antibodies. The selected bleeds must be characterized for reactivity with intact BIOLOGIC A and human PTH (natural endogenous version). This can include direct binding and competitive inhibition testing. The accepted reagent must be sensitive for detection of BIOLOGIC A and the human PTH. Ideally the reagent must have low or no cross-reactivity with human PTH.

The Contractor shall complete the polyclonal anti-BIOLOGIC A antibody generation (including specificity testing) within three to six months following the effective date of this task order.

ii. Purification and Labeling Characterization

Once acceptable sera have been collected, the Contractor shall produce purified anti- BIOLOGIC A antibody. Depending on the results of specificity/cross-reactivity testing, the antibody can be purified as total immunoglobulin (i.e. protein A), or, if necessary to achieve appropriate specificity, using specific affinity purification/depletion methods. A fraction of purified antibody must be labeled for use as an assay reagent (e.g. with biotin or ruthenium). Several labeling conditions may be requested for testing by NCATS prior to selecting the final condition. Purified and labeled reagents must be characterized for

a) concentration, b) purity, c) % recovery of binding activity vs unpurified/unlabeled and

d) molecular weight and aggregates. The final amount requested is 10 - 50 mg of each critical assay reagent.

The Contractor shall complete the purification and labeling characterization within one month following completion of the polyclonal anti-BIOLOGIC A antibody generation.

iii. Monoclonal Anti-BIOLOGIC A Antibody Generation

Animals should be immunized with one or more appropriate immunogens (number of immunogens and immunization regimen should be proposed by the offeror and agreed to by NCATS) as required to assure generation of a specific, high titer antibody response.

Serial bleeds (test bleeds) should be collected and titered for reactivity with BIOLOGIC A.

Once a suitable titer has been achieved, animals will be boosted once more and hybridization can commence. Hybridization supernatants should be tested for reactivity with intact BIOLOGIC A and positive clones should be characterized for cross-reactivity with human PTH (natural endogenous version). This can include direct binding and competitive testing. The accepted reagent(s) should be sensitive for detection of BIOLOGIC A. Ideally the reagent should have low cross-reactivity with human PTH and at least one reagent antibody should have neutralizing antibody activity. The acceptable clone(s) should be expanded to collect supernatant for purification.

The Contractor shall complete the monoclonal anti-BIOLOGIC A antibody generation (including specificity testing) within four to eight months following the effective date of this task order.

iv. Purification and Labeling

Once one or more acceptable clones have been collected, purified anti-BIOLOGIC A antibody should be produced using protein A or other appropriate affinity purification methods. One or more purified antibodies should be labeled for use as an assay development reagent (e.g. with biotin or ruthenium). Several labeling conditions may be requested for testing by the client prior to selecting the final condition. Purified and labeled reagents should be characterized for a) concentration, b) purity, c) % recovery of binding activity vs unpurified/unlabeled and d) molecular weight and aggregates. The final amount requested is 10 - 50 mg of each critical assay reagent.

The Contractor shall complete the purification and labeling within one month following completion of the monoclonal anti-BIOLOGIC A antibody generation.

v. Project Management

The Contractor shall provide project management for its own core team to ensure planning, execution, delivery of reports, and accurate and timely communication with the Contracting Officer’s Representative (COR), Contracting Officer (CO), and other stakeholders.

The Contractor shall manage either face-to-face or telephone team meetings on a biweekly basis, to keep the COR and the project team apprised of project progress including any issues or problems. The Contractor shall be responsible for securing a physical location for the meeting or a suitable call in number and passcode for the relevant participants and be responsible for moderating the meeting.

At least twenty-four hours prior to the team meeting, the Contractor shall submit a Pre-meeting Status Report that documents the efforts performed in the completion of each task. The Pre-meeting Status Reports shall include, at a minimum, the following information:

- Program status, to include objectives met, work completed, and outstanding work.

- Notable achievements.

- Issues or obstacles impeding progress and recommended solutions.

- Description of work completed and plans for next reporting period.

- Agenda for corresponding team meeting.

- Status of deliverables/milestones.

- Issues and resolutions.

- Resource planning/status.

Within forty-eight hours following the team meeting, the Contractor shall submit Post- Meeting Minutes that includes, at a minimum, a summary of any action items resulting from the meeting. The Contractor shall deliver the Pre-meeting Status Report and the Post-Meeting Minutes to all meeting participants via secure e-mail.

In addition, the Contractor shall immediately contact the COR if there are any adverse results or difficulties with the study that would impact the project or timeline. The communications shall include proposed solutions.

vi. Standard Operating Procedures

The Contractor shall follow all site-specific standard operating procedures (SOPs); or if a deviation from an SOP is required, notify the COR of the deviation and document as appropriate. At the request of the COR, the Contractor shall submit to the Government any SOPs, method descriptions, and references used in the implementation of studies.

The Government will treat Contractor SOPs as confidential.

vii. Transition Plan

At least forty-five calendar days prior to task order expiration, the Contractor shall provide the COR with a proposed Transition Plan for an orderly and complete transition/relocation of the task order resources to a successor Contractor or to the Government. The plan shall include details on the relocation/disposition of: unused materials and supplies; manuals and directories developed by the Contractor; and all other government property not listed. Upon written direction by the Government, the Contractor shall transfer all Government property as directed, and fully cooperate with any successor Contractor and the Government to ensure an efficient transfer.

4. Research Involving Live Vertebrate Animals

The animals used under this task order shall be obtained from an AAALAC-accredited registered breeder (Association for Assessment, Accreditation, and Laboratory Animal Care). These requirements are in addition to the requirements included in the Care of Live Vertebrate Animals and Animal Welfare Articles set forth in Section H of the parent IDIQ contract.

5. Government-Furnished Data

The Contractor will have access to any data available at NCATS or the NCATS partner related to each task order that the Government deems necessary to successfully perform under the task order.

The Government will ensure all candidate therapeutics and any known safety data for storage and handling are supplied to the Contractor.

E. Task order Report and Delivery Schedule

Satisfactory performance of the task order shall be deemed to occur upon performance of the work described in the TO award, and upon completion, delivery, and acceptance by the Contracting Officer, or duly authorized representative, the below listed deliverables. The deliverables shall be delivered F.o.b. Destination as set forth in FAR Clause 52.247-35, F.o.b.

DESTINATION, WITHIN CONSIGNESES PREMISES (APRIL 1984).

Item Description Delivery Method

Delivery Schedule

1 Polyclonal anti-BIOLOGIC A Antibody (including specificity testing)

As directed by the COR

3-6 months following the effective date of the task order

2 Purification and Labeling Characterization

As directed by the COR

1 month following the delivery of the Polyclonal Anti-BIOLOGIC A Antibody

3 Monoclonal anti- BIOLOGIC A antibody generation (including specificity testing)

As directed by the COR

4-8 months following the effective date of the task order

4 Purification and labeling As directed by the COR

1 month following the delivery of the Monoclonal Anti-BIOLOGIC A Antibody

5 Pre-Meeting Status Report

Electronically to the COR

At least 24 hours prior to Team Meeting

6 Post-Meeting Minutes Electronically to the COR

Within 48 hours following Team Meeting

7 Report of Adverse Results or Difficulties

Electronically to the COR

Immediately upon event

8 Standard Operating Procedures

Electronically to the COR

Upon request

9 Transition Plan Electronically to COR & CO

At least 45 calendar days prior to TO expiration

F. Task Order Technical Proposal Instructions

Your task order technical proposal shall address the requirements as set forth in this TORFP and the TO SOW and be included in your Technical Proposal for the Parent IDIQ Contract. In addition, your task order technical proposal should be structured as follows:

1. Cover Sheet

The Technical Proposal cover sheet should include the following:

i. Contract number.

ii. Task order RFP number.

iii. Task order title.

iv. Name, address, email, and telephone number of Principal Investigator.

v. Date of submission.

vi. Name, title, address, email, telephone number, and signature of authorized Business Representative (person authorized to sign contracts on behalf of your organization).

2. Executive Summary

Provide the most important elements from the sections below. At a minimum, clearly specify the following elements:

i. Brief identification and qualifications for this solicitation of your organization/team, including any subcontractors and their roles.

ii. The purpose and anticipated end-result of your proposal.

iii. Technical and management approach discriminators.

The summary should be on separate pages or include a section break before the rest of the proposal.

3. Technical Approach/Methods

i. Understanding

Provide your understanding of what needs to be done, the scope of work, the estimated length of time for the work to be completed, and the challenges and how you will address those challenges.

ii. Approach

Describe your technical approach to the proposed work. Describe critical technology challenges required for accomplishing your proposed tasks. Describe any unique aspects of your technical approach. Describe why you believe your technical approach will be the most efficient and effective way of achieving project objectives. Describe how your technical approach will meet both project and overall objectives as described in this TORFP.

4. Team and Key Personnel

i. Introduction

Introduce your organization and/or team. Give an overview of the capabilities brought to address this effort.

ii. Organization and/or Team

Describe your organization and show chain of command and lines of communication.

Describe each proposed individual’s role and the percentage of their time that is being proposed and a brief description of their qualifications. Provide more detailed experience descriptions and resumes as an appendix to your technical proposal. Note who is responsible for development of the drug formulation and provide their experience. Also note who will carry out the stability studies on the trial formulations and who will carry out the final product release testing on the finished drug product.

iii. Key Personnel

At least two key personnel are required and shall be clearly indicated. Include resumes or summaries for key personnel in this section; include full resumes as an appendix to your technical proposal. Clearly indicate the percentage of time proposed for each key personnel.

5. Experience and Past Performance

Describe the team’s overall experience with development, processes, and technologies like those described in the SOW. Clearly indicate which members of your team is providing this experience.

Provide a summary description of at least three past projects successfully performed that indicate your ability to perform on this effort. Clearly indicate who on your team played a role in each of these projects and describe what role they played. Clearly indicate the success criteria that were used to judge these projects. More detailed descriptions of these past projects may be provided as an appendix to your technical proposal.

6. Facilities

Provide information demonstrating that the following requirements will be met:

i. The facilities are appropriate for handling clinical grade Drug Products under cGMPs.

ii. The equipment calibration and maintenance program will comply with applicable U.S.

FDA guidelines.

Clearly delineate which activities will be performed with internal capabilities and which activities will be outsourced. For the activities that will not be performed in-house, list the organizations that will carry out the out-sourced responsibilities/tests, the basis for their selection, and audit history of those organizations. Any out-sourced testing must be QA audited and approved by the TO awardee.

7. Project Plan and Work Breakdown Structure

Summarize the tasks that will be performed to accomplish the project objectives.

Detail the method for producing deliverables, allocation of staff, timelines, and other resources necessary to produce the deliverables.

Provide a draft project plan in MS Project format as a separate attachment (no page limit).

The plan should contain tasks that demonstrate how objectives described in the SOW will be accomplished. The plan should also show tasks, dependencies, milestones, any milestones reviews as requested in this TORFP, and any requested Offeror-supplied dates for deliverables.

8. Management Approach

i. Controls

Describe your project management approach and what control mechanisms will be implemented to track progress and ensure agreed-upon schedules are kept.

ii. Risk Management

Describe your overall risk mitigation strategy.

Provide an initial risk table which includes a list of project risks, an estimation of the severity of the risk (HML), and a corresponding, brief mitigation approach.

iii. Subcontractor Management

If subcontractors are proposed, describe the management controls to be implemented for subcontractor management.

iv. Financial Tracking

Describe the mechanism you will use to control budget and cost.

9. Research Involving Live Vertebrate Animals

It is intended that live vertebrate animals will be used during performance of this task order.

The Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (authority derived from the Health Research Extension Act of 1985) specifies that certain information is required from offerors in proposals submitted to the NIH that will use liver vertebrate animals.

Address the following criteria in a separate section of the Task Order Technical Proposal titled “Vertebrate Animal Section”:

i. Description of Procedures

Provide a concise description of the proposed procedures to be used that involve vertebrate animals in the work outlined in the Request for Proposal (RFP) Statement of Work. Identify the species, strains, ages, sex and total number of animals by species to be used in the proposed work. If dogs or cats are proposed, provide the source of the animals.

ii. Justifications

Provide justification that the species are appropriate for the proposed research. Explain why the research goals cannot be accomplished using an alternative model (e.g., computational, human, invertebrate, in vitro).

iii. Minimization of Pain and Distress

Describe the interventions including analgesia, anesthesia, sedation, palliative care and humane endpoints to minimize discomfort, distress, pain and injury.

iv. Euthanasia

State whether the method of euthanasia is consistent with the recommendations of the American Veterinary Medical Association (AVMA) Guidelines for the Euthanasia of Animals. If not, describe the method and provide a scientific justification.

A concise (no more than 1-2 pages), complete description addressing these criteria must be provided. The description must be cohesive and include sufficient information to allow evaluation by reviewers and NIH staff. For more discussion regarding the VAS, see NIH Guide Notice NOT-OD-16-006 at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16- 006.html .

The Contract Proposal VAS Worksheet is provided as an Attachment in SECTION J of this solicitation to assist in the preparation of the VAS as part of the Technical Proposal. It can be accessed at: http://grants.nih.gov/grants/olaw/VAScontracts.pdf .

10. Subcontracts http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-006.html http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-006.html http://grants.nih.gov/grants/olaw/VAScontracts.pdf

If you are proposing subcontracts to carry out tasks under this TO, provide a justification why this work cannot be performed at the Contractor’s site using their personnel, and why it must be subcontracted. In addition, provide the tasks to be subcontracted, the name and location of the subcontractor, basis for their selection, and an audit history of the subcontractor in carryout similar tasks/tests for the contractor.

The Prime’s proposal must include a discussion of how they determined that the proposed subcontractor is technically qualified to perform that portion of the work, and further they must discuss their cost analysis of the subcontractor’s proposal to determine that it is both technically acceptable and offered at a fair and reasonable cost.

The Prime Contractor shall also obtain from the subcontractor a commitment letter from the proposed subcontractor detailing the following:

i. Willingness to perform as a subcontractor for specific duties (list duties).

ii. What priority the work will be given and how it will relate to other work.

iii. The amount of time and facilities available to this project.

iv. Information on their cognizant field audit offices.

v. How rights to publications and patents are to be handled.

vi. A complete cost proposal in the same format as the offeror's cost proposal.

11. Direct Costs and Resources Information

Your technical proposal must include direct cost and resources information, such as labor-hours and categories and applicable rates, materials, subcontracts, travel, etc. and associated costs. However, the technical proposal should not include pricing data relating to individual salary information, indirect cost rates or amounts, fee amounts (if any), and total costs.

G. Business Proposal Instructions

Your task order business proposal shall be included in your Business Proposal for the Parent IDIQ Contract. In addition, your task order business proposal should be structured as follows:

1. Cover Sheet

The business proposal cover sheet should include the following:

i. Contract number.

ii. Task order RFP number.

iii. Task order title.

iv. Name, address, email, and telephone number of Principal Investigator.

v. Date of submission.

vi. Name, title, address, email, telephone number, and signature of authorized Business Representative (person authorized to sign contracts on behalf of your organization).

2. Basic Cost/Price Information

Offerors should propose a payment schedule by project milestone and include the payment amount for each milestone.

The payment schedule must be supported by sufficient information to allow the Government to perform a basic cost analysis and/or price analysis of the proposed price offered for each milestone. This information shall include the amounts of the basic elements of the proposed cost or price. Basic elements include: direct labor, materials/supplies, indirect costs, subcontracted items, other direct costs, etc.

3. Subcontracts

If you are proposing subcontractor(s) for this TO proposal, you must submit separate budget spreadsheets, narrative, and supporting documentation to verify price/costs proposed for the subcontract in the same manner as required herein for your organization’s price/cost.