RFP_17-01_and_all_Attachments.pdf

RFP NIH-NINDS 17-01

SOLICITATION

SECTION A - SOLICITATION/CONTRACT FORM

1.Requisition or other Purchase Authority: 42 U.S.C. 285 j

2. Request for Proposal (RFP) Number:

NIH-NINDS-17-01

3. Issue Date:

July 17, 2017

4. Set Aside:

[X] No [ ] Yes See Part IV SECTION L

5. Title: “Medicinal Chemistry Support Program for Therapeutic Development (MCSP)”

6. ISSUED BY:

National Institute of Neurological Disorders and Stroke

R&D Contracts Management Branch, Office of Acquisitions, NIDA National Institutes of Health Neuroscience Center 6001 Executive Blvd., Suite 3287 Rockville, MD 20852

7. SUBMIT OFFERS TO:

See Part III, Attachment in Section J, “Packaging and Delivery of Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website.”

Offers are to be submitted electronically via the NIH (eCPS) website at:

https://ecps.nih.gov

8. Proposals for furnishing the supplies and/or services in THE SCHEDULE will be received at the place and in the number of copies specified in Attachment “Packaging and Delivery of Proposals” until 5:00 p.m. local time on MONDAY, August 18, 2017.

Offers will be valid for 150 days unless a different period is specified by the offeror in the Attachment entitled, "Proposal Summary and Data Record, NIH-2043.”

9. This solicitation requires delivery of proposals to be submitted electronically via the NIH (eCPS) website at: https://ecps.nih.gov . Offerors are responsible for completing the registration process and establishing an account in the NIH Electronic Contract Proposals Submission (eCPS) system/website in order that their proposal is received by 5:00 pm local time on August 18, 2017.

If your proposal is not received by the specified proposal submission time and date, then it will be considered “Late” and handled in accordance with HHSAR Clause 352.215-70, “Late proposals and Revisions,” addressed in Section L.1, paragraph (k) of the RFP.

10. Offeror must be registered in the System for Award Management (SAM) prior to award of a contract. Offerors can access SAM at: http://www.sam.gov

11. FOR INFORMATION CALL: Annette Carter, Contracting Officer

PHONE: 301-496-1813 – (COLLECT CALLS WILL NOT BE ACCEPTED.)

e-MAIL: cartera@mail.nih.gov

Kirkland L. Davis Office of Acquisition, Neurosciences Chief, NINDS R&D Contracts Management Branch, NIDA, NIH https://ecps.nih.gov/ https://ecps.nih.gov/ http://www.sam.gov/ mailto:cartera@mail.nih.gov

RFP TABLE OF CONTENTS

PART I – THE SCHEDULE

SECTION A - SOLICITATION/CONTRACT FORM

SECTION B - SUPPLIES OR SERVICES AND PRICES/COSTS

SECTION C - DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

SECTION D - PACKAGING, MARKING AND SHIPPING

SECTION E - INSPECTION AND ACCEPTANCE

SECTION F - DELIVERIES OR PERFORMANCE

SECTION G - CONTRACT ADMINISTRATION DATA

SECTION H – SPECIAL CONTRACT REQUIREMENTS

PART II - CONTRACT CLAUSES

SECTION I – CONTRACT CLAUSES

PART III - LIST OF DOCUMENTS, EXHIBITS AND OTHER ATTACHMENTS

SECTION J - LIST OF ATTACHMENTS

PART IV - REPRESENTATIONS AND INSTRUCTIONS

SECTION K - REPRESENTATIONS, CERTIFICATIONS AND OTHER STATEMENTS OF OFFERORS

SECTION L - INSTRUCTIONS, CONDITIONS, AND NOTICES TO OFFERORS

1. GENERAL INFORMATION

a. Instructions to Offerors-Competitive Acquisition

b. NAICS Code and Size Standard

c. Type of Contract and Number of Awards

d. Task Orders Under Multiple Award Indefinite Delivery Contracts

e. Estimate of Effort

f. Commitment of Public Funds

g. Communications Prior To Contract Award

h. Release of Information

i. Preparation Costs

j. Service of Protest

k. Late Proposals and Revisions

2. INSTRUCTIONS TO OFFERORS …

a. GENERAL INSTRUCTIONS

1. Contract Type and General Clauses

2. Authorized Official and Submission of Proposal

3. Proposal Summary and Data Record (NIH-2043)

4. Separation of Technical and Business Proposals

5. Alternate Proposals

6. Evaluation of Proposals

7. Potential Award Without Discussions

8. Use of the Metric System of Measurement

9. Privacy Act - Treatment of Proposal Information

10. Selection of Offerors

11. Institutional Responsibility Regarding Investigator Conflicts of Interest

12. ROTC Access and Federal Military Recruiting on Campus

13. Past Performance Information

14. Information and Physical Access Security

15. Solicitation Provisions Incorporated by Reference

b. TECHNICAL PROPOSAL INSTRUCTIONS

1. Proposal Format Instructions …

2. Technical Proposal Overview

3. Technical Capabilities and Discussions

4. Technical Proposal Evaluation

5. Technical Proposal Budget Templates

6. Other Technical Proposal Considerations

c. BUSINESS PROPOSAL INSTRUCTIONS

1. Proposal Format Instructions

2. Business Proposal Budget Templates

3. Uniform Assumptions

4. Basic Cost/Price Information

5. Other Business Proposal Requirements

SECTION M - EVALUATION FACTORS FOR AWARD

PART I - THE SCHEDULE

THE INFORMATION SET FORTH IN SECTION A - SOLICITATION/CONTRACT FORM, HEREIN

CONTAINS IMPORTANT INFORMATION FOR ANY OFFEROR INTERESTED IN RESPONDING

TO THIS SOLICITATION. ANY CONTRACT RESULTING FROM THIS SOLICITATION WILL

INCLUDE IN ITS SECTION A - SOLICITATION/CONTRACT FORM, ACCOUNTING,

APPROPRIATION AND GENERAL INFORMATION APPLICABLE TO THE CONTRACT AWARD.

THE CONTRACT SCHEDULE SET FORTH IN SECTIONS B THROUGH H, HEREIN, CONTAINS

CONTRACTUAL TERMS AND CONDITIONS AND INFORMATION PERTINENT TO THIS

SOLICITATION. IT IS NOT AN EXACT REPRESENTATION OF THE CONTRACT DOCUMENT

THAT WILL BE AWARDED AS A RESULT OF THIS SOLICITATION. THE CONTRACT COST OR

PRICE AND OTHER CONTRACTUAL TERMS THAT MAY BE PERTINENT TO THE OFFEROR

(i.e., those relating to the organizational structure [e.g., Non-Profit, Commercial] and specific cost authorizations unique to the Offeror's proposal and requiring Contracting Officer Prior Approval)

WILL BE DISCUSSED IN THE NEGOTIATION PROCESS AND WILL BE INCLUDED IN THE

RESULTANT CONTRACT. THE FOLLOWING CONTRACT SCHEDULE IS INTENDED TO

PROVIDE THE OFFEROR WITH THE NECESSARY INFORMATION TO UNDERSTAND THE

TERMS AND CONDITIONS THAT ARE GERMANE AND INTENDED TO BE

ADDRESSED/INCLUDED IN ANY RESULTANT CONTRACT.

SECTION B - SUPPLIES OR SERVICES AND PRICES/COSTS

ARTICLE B.1. - BRIEF DESCRIPTION OF SUPPLIES OR SERVICES

The National Institute on Neurological Disorders and Stroke (NINDS) is pursuing Multiple Award Indefinite Delivery/Indefinite Quantity (ID/IQ) type contracts to provide neuroscientists with medicinal chemistry services to develop preclinical drug candidates/optimized drug leads that are ready for Investigational New Drug (IND) enabling pharmacology and toxicology studies. Under the auspices of the NIH Blueprint for Neuroscience Research Program, and more specifically the NIH Blueprint Neurotherapeutics Network (BPN), (http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm), the Medicinal Chemistry Support Program for Therapeutic Development (MCSP) provides a critical component of the BPN drug development infrastructure.

Although the NINDS focus is on neurotherapeutics it is envisioned the other ICs may on occasion access this contract for small molecule therapeutics other than neurotherapeutics. The data generated from this contract will be used by NINDS, contributors or sponsored investigators in support of Investigational New Drug (IND) application directed preclinical activities. The results of the efforts of this contract will be the basis to advance preclinical candidate compounds for further development i.e., advanced PK and toxicological evaluation in preparation of IND filings. In addition, this contract can serve and be utilized for individual development projects outside the Blueprint Network.

ARTICLE B.2. - PRICES/COSTS

a. This is a Multiple Award Indefinite Delivery/Indefinite Quantity (ID/IQ) contract as contemplated by FAR

16.504. Any resultant ID/IQ contract award will contain a guaranteed minimum of $25,000. The estimated maximum amount will be $39,500,000 during the 10-year ordering period of this contract.

b. This ID/IQ contract has a total ordering period of 10 years. As necessary, NINDS will issue Task Orders for the Contractor to perform any or all of the Performance Activities listed in the Statement of Work (SOW). For this ID/IQ award, the NINDS intends to issue Task Order #001 for Performance Area 1, “Tech Transfer, Storage Handling and Distribution, Access Training and IT Security Relevant to Existing Compound Repository” concurrent with this award. This task order award will obligate the total price negotiated for the first year of performance under Performance Area 1. This will be a fixed-price type Task Order with a term of 12 months and will contain nine (9) annual 12-month term options. The total fixed-price amount negotiated for each year under the Performance Area 1 Task Order will be equally divided by the number of report deliverables specified for that period to establish a fixed-price per report deliverable amount. Payments will be made upon delivery and acceptance for these report deliverables.

Amounts negotiated for Task Order #001, Performance Area 1, “Tech Transfer, Storage Handling and Distribution, Access Training and IT Security Relevant to Existing Compound Repository " plus all possible options, is as follows:

Contract Line Item Number (CLIN) and Description

Period of Performance

Amount ($)

CLIN 1 – Task Order #001 – Year 01 (12 months) Performance Area 1, “Tech Transfer, Storage Handling and Distribution, Access Training and IT Security Relevant to Existing Compound Repository

January 2018 – January 2019

CLIN TBD - Option No. 1 - Year 02 (12 months) January 2019 – January 2020

CLIN TBD - Option No. 2 - Year 03 (12 months) January 2020 – January 2021

CLIN TBD - Option No. 3 - Year 04 (12 months) January 2021 – January 2022

CLIN TBD - Option No. 4 - Year 05 (12 months) January 2022 – January 2023 http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm

CLIN TBD - Option No. 5 - Year 06 (12 months) January 2023 – January 2024

CLIN TBD - Option No. 6 - Year 07 (12 months) January 2024 – January 2025

CLIN TBD - Option No. 7 - Year 08 (12 months) January 2025 – January 2026

CLIN TBD - Option No. 8 - Year 09 (12 months) January 2026 – January 2027

CLIN TBD - Option No. 9 - Year 10 (12 months) January 2027 – January 2028

Amounts for the base/initial Task Order and for each 12-month term option, if exercised, will be tracked separately with disbursements to correspond to the 12-month period in which those funds are properly chargeable.

c. Task Orders for Performance Area 2, “Medicinal Chemistry Support (MCS)”, for individual MCS studies will be competed through a Task Order Request for Proposals (TORFPs) process as the need arises. It is anticipated that these task orders will be cost-reimbursement, completion-type task orders and will have variable periods of performance.

d. Ordering procedures under this contract will be as described in Article G.3., Task Order Procedure, of this contract.

ARTICLE B.3. - PROVISIONS APPLICABLE TO DIRECT COSTS

This article will prohibit or restrict the use of contract funds, unless otherwise approved by the Contracting Officer. The following is a list of items that may be included in the resultant contract as applicable. 1) Conferences & Meetings, 2) Food for Meals, Light Refreshments & Beverages, 3) Promotional Items, 4) Acquisition, by purchase or lease, of any interest in real property; 5) Special rearrangement or alteration of facilities; 6) Purchase or lease of any item of general purpose office furniture or office equipment regardless of dollar value; 7) Travel Costs including Foreign Travel; 8) Consultant Costs; 9) Subcontract Costs; 10) Patient Care Costs; 11) Accountable Government Property; 12) Printing costs; and 13) Research Funding.

ARTICLE B.4. - ADVANCE UNDERSTANDINGS

Specific elements of cost, which normally require prior written approval of the Contracting Officer before incurrence of the cost (e.g., foreign travel, consultant fees, subcontracts), will be included in this Article if the Contracting Officer has granted his/her approval prior to contract award.

a. Confidential Treatment of Sensitive Information

The Government has determined that the information/data that the Contractor will be provided during the performance of the contract is of a sensitive nature. The Contractor shall guarantee strict confidentiality of the information/data that it is provided by the Government during the performance of the contract.

Disclosure of the information/data, in whole or in part, by the Contractor can only be made after the Contractor receives prior written approval from the Contracting Officer. Whenever the Contractor is uncertain with regard to the proper handling of information/data under the contract, the Contractor shall obtain a written determination from the Contracting Officer.

b. Non-Personal Services and Inherently Government Functions

Pursuant to FAR 37.1, no personal services shall be performed under this contract. All work requirements shall flow only from the Contracting Officer's Technical Representative (COR) to the Contractor's Project Manager. No Contractor employee will be directly supervised by the Government. All individual employee assignments, and daily work direction, shall be given by the applicable employee supervisor. If the

Contractor believes any Government action or communication has been given that would create a personal services relationship between the Government and any Contractor employee, the Contractor shall promptly notify the Contracting Officer of this communication or action.

Pursuant to FAR 7.5, the Contractor shall not perform any inherently Governmental actions under this contract. No Contractor employee shall hold him or herself out to be a Government employee, agent, or representative. No Contractor employee shall state orally or in writing at any time that he or she is acting on behalf of the Government. In all communications with third parties in connection with this contract, Contractor employees shall identify themselves as Contractor employees and specify the name of the company for which they work. In all communications with other Government contractors in connection with this contract, the Contractor employee shall state that they have no authority to in any way change the contract and that if the other contractor believes this communication to be a direction to change their contract, they should notify the Contracting Officer for that contract and not carry out the direction until a clarification has been issued by the Contracting Officer.

The Contractor shall insure that all of its employees working on this contract are informed of the substance of this article. Nothing in this article shall limit the Government's rights in any way under the other provisions of the contract, including those related to the Government's right to inspect and accept the services to be performed under this contract. The substance of this article shall be included in all subcontracts at any tier.

c. Contract Number Designation

On all correspondence submitted under this contract, the Contractor agrees to clearly identify the contract number that appears on the face page of the contract as follows:

Contract No. ___________________

d. Site Visits

The NINDS anticipates making visits to the Contractor facility. Contractor shall be responsible for making the facility available for a visit and arranging meetings with appropriate personnel. The Contractor may be required to make an approved reverse site visit to Bethesda, Maryland to meet with NINDS staff.

SECTION C - DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

ARTICLE C.1. - STATEMENT OF WORK

1. Introduction/Background

The National Institute on Neurological Disorders and Stroke (NINDS) and the NIH Blueprint Neurotherapeutics Network (BPN) http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm have established a virtual pharma network of contract service providers and consultants with extensive industry experience to enable small molecule, peptide and biologic therapeutics discovery and development in the National Institutes of Health (NIH) community. NINDS and the BPN have a need to re-compete its full service, turn-key medicinal chemistry operations for the development of therapeutics within the mission of NINDS, BPN and other NIH Institutes and Centers (ICs). This full-service facility and staff would support a range of medicinal chemistry services including structure activity relationship (SAR) analysis and design, synthesis, in vitro absorption, distribution, metabolism, excretion and toxicology (ADMET), computational chemistry/Computer Aided Drug Discovery (CADD) and compound logistics of storage and shipping. The BPN, and other NINDS and NIH programs offer researchers access to a range of industry-standard services and expertise including full service medicinal chemistry services, pharmacokinetics/toxicology, drug manufacturing and formulation and Phase I clinical testing. Projects may access some or all of this NIH infrastructure.

The term neurotherapeutics includes therapies targeted to indications due to disorders of the central and/or peripheral nervous system, and shall include novel agents developed by the NIH and its grantees (henceforth known as the “Contributor (s)”) and provided to the NINDS for collaborative development as well as investigational agents supported through the NINDS including the BPN and other Institutes or Centers (ICs).

Although the NINDS focus is on neurotherapeutics it is envisioned the other ICs may on occasion access this contract for small molecule therapeutics other than neurotherapeutics. The data generated from this contract will be used by NINDS, contributors or sponsored investigators in support of Investigational New Drug (IND) application directed preclinical activities. The results of the efforts of this contract will be the basis to advance preclinical candidate compounds for further development i.e., advanced PK and toxicological evaluation in preparation of IND filings.

The ultimate goal of the NIH programs served by this contract and of individual projects is to bring new drugs to market. To this end, the NIH has been granted a Determination of Exceptional Circumstances (DEC) to incorporate the Department of Health and Human Services Acquisition Regulation (HHSAR) clauses at 352.227-11, Patent-Rights-Exceptional Circumstances and 352.227-14, Rights in Data – Exceptional Circumstances, as part of any contract resulting from this solicitation. The HHSAR Clauses will enable the Contributors to retain control of the intellectual property for compounds created through the Medicinal Chemistry Support Program for Therapeutic Development (MCSP).

2. Scope

The scope of this MCSP contract shall be medicinal chemistry services including project management and reporting, compound logistics, synthesis, computational chemistry and in vitro ADMET studies in support of preclinical drug discovery efforts supported by NIH, NINDS and its contributors. The work may include any individual service or combinations of services described (e.g. Synthesis, CADD, ADMET individually or in combination).

The Contractor must have the capacity to conduct from 1-10 projects simultaneously in the three chemistry stages as outlined below (exploratory, hit-to-lead, lead optimization). The Contractor shall also have available sufficient professional and technical personnel, facilities and the capability to rapidly scale up or down the number of staff dedicated to the MCSP contract, depending on the number of projects underway at any given time.

3. Contract Type and Ordering Mechanism

The Government intends to award indefinite delivery/indefinite quantity (ID/IQ) contracts to 1-2 sources.

These contracts will be administered and funded via Task Orders (TO). The ID/IQ Contractors shall compete for future MCSP studies as requirements become available. The Contractor shall perform the tasks if and as directed in awarded Task Orders. Task Order awards will cover the following performance areas:

http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm

i) Performance Area 1: Tech Transfer, Storage Handling and Distribution, Access Training and IT Security Relevant to Existing Compound Repository - will cover the effort needed for contract start-up and project management, consultation and communication with NIH, BPN members and other NIH designated individuals, implementation and maintenance of data management functions, logistics of compound management, preparation and delivery of administrative and technical reports and the development of potential transition plans. The Task Order for Performance Area 1 will be fixed priced with a term of one year. The initial Task Order will also contain nine annual one-year term options. The additional nine term options would provide for continuation of work under this Performance Area for each successive year of the ten (10) year ID/IQ order period at the election of the Government.

ii) Performance Area 2: Medicinal Chemistry Support (MCS). Task orders for individual MCS studies will be competed through a Task Order Request for Proposals (TORFPs) process under Performance Area 2 as requested. It is anticipated that these task orders will be cost-reimbursement, completion-type task orders and will have variable periods of performance.

NINDS anticipates issuing 1-6 TORFPs under Performance Area 2 during each year of the contract. The actual number of TORFPs issued will depend upon programmatic needs and funding availability, and will vary from year to year. Due to changes in priorities within NINDS, the projected workload cannot be precisely described for each year. The Contractor shall initiate work only when authorized by issuance of an approved task order.

Project Capacity Estimate: The NINDS anticipates requiring Medicinal Chemistry Support (medicinal Chemistry synthesis, in vitro ADMET, computational chemistry) for up to 10 projects per year under Performance Area 2. Not all projects will require all stages/components. It is anticipated that multiple projects will be conducted concurrently.

4. Specific Technical Requirements

The Government will be responsible for providing the following:

• NIH staff: The NINDS Contracting Officer (CO) and Contracting Officer Representative (COR) will oversee the medicinal chemistry contract. The COR will offer suggestions and provide feedback to the Contractor on medicinal chemistry strategies and project design, in consultation with the Contributors and NIH-hired medicinal chemistry consultants (see below).

• Researchers (Contributors) with bioactive small molecule compounds and bioactivity assays: The Contributors’ compounds will serve as starting points for medicinal chemistry. The Contributors, using their own bioactivity assays, will test compounds provided by the medicinal chemistry efforts of the Contractor or the Contributor. Contributors will be selected by the NIH through a competitive process and supported through a cooperative agreement mechanism or by other programmatic methods by NIH. All interactions between the Contractor and Contributors will be mediated and managed by the

COR.

• Access to reports of PK and PD assays used in preclinical development as needed.

• Additional scientific information on the analogs as needed to execute the services under this contract.

• Medicinal chemistry consultants: The NIH will hire consultants to assist the COR in reviewing proposals, reports, and data produced by the Contractor and Contributors.

• Information Technology (IT) system: The NIH will establish a database and user-friendly interface for entering, searching, downloading, and visualizing medicinal chemistry data. The medicinal chemistry Contractor and Contributors will be responsible for entering the data that they generate into this database. All MCSP participants will receive training on how to use the IT system and technical support. Information on an ongoing basis related to the biological potency/efficacy and selectivity evaluation in support SAR studies will be available via this interface.

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government, as needed, to conduct services in the following Performance Areas.

4.1 Performance Area 1: Tech Transfer, Storage Handling and Distribution, Access Training and IT Security Relevant to Existing Compound Repository

Under this Performance Area, the Contractor shall perform all activities related with overall administration and implementation of the medicinal chemistry support services including but not limited to the setup for project management, overall contract management, technical preparedness and support, communications and submission of deliverables under the contract and the ongoing delivery of project reports and compound management logistics.

Performance responsibilities under Performance Area 1 include but are not limited to:

a. The Contractor shall provide a Principal Investigator (PI) who is primarily responsible and accountable for the overall implementation of the awarded contract, who serves as the central point of contact for scientific and technical aspects of the contract and has significant experience in the conduct of Medicinal Chemistry and supporting activities. The PI shall possess a PhD chemistry degree and at least 10 years of managing a group of medicinal chemists.

b. The Contractor shall assemble a team with all the required core expertise including but not limited to medicinal chemists, ADMET scientists, computational scientists, compound management and support staff. The Government expects the Contractor to provide the majority of the services at its own institution. The Contractor shall have established facilities and research infrastructure, with the appropriate number and mix of personnel to conduct multiple concurrent projects as required under this contract without delay in initiation after task order awards.

c. In order to bid and perform activities under Performance Area 2 the Contractor will be initially required to complete and sign a Non-Disclosure agreement relating to confidential information provided by the Government as a part of any Task Order Request for Proposal (TORFP) issued under Performance Area 2.

d. Contractor shall be required to properly provide data to the NIH via NIH’s compound/biology relational database system. The Government will provide guidance and/or training in accessing and uploading of compound data and accompanying biological data and reports to the NIH database, currently provided by Collaborative Drug Discovery (CDD), on a per project basis even when data is run concurrently for multiple projects to meet the program to meet for technical, data management and other support staff to meet all Government requirements under the contract is needed;

e. Contractor shall comply with Information Technology preparedness, training, non-disclosure agreements, and security requirements as set forth below and in other articles of this contract, e.g., FISMA and 508 of the Rehabilitation Act of 1973, as amended by the Workforce Investment Act of 1998. Since the Contractor will be using their own equipment for data entry functions and operations under the contract, in order to ensure the security and protection of the data in these operations, the Contractor agrees to and shall implement the following:

• Any contractor computer used in this contract shall be patched with the most updated IT Security Patches.

• Any contractor computer used in this contract shall have virus protection loaded and running with definition files that are updated on at least a daily basis.

• Hard drives and portable media used for this contract shall be encrypted using the FIPS 140-2 standard.

• Any computers used on the contract shall be assessed for vulnerabilities.

• Any computers used on the contract shall be backed up.

• Any computers used on the contract shall be managed by a configuration control plan.

• Any computers used on this contract shall have auditing enabled such that if an incident occurred then that event could be reconstructed.

• Any computers that are used in this contract must employ at a minimum user name and password authentication or if possible two factor authentication. In this regard, all passwords must meet the NIH standard and users must choose passwords that have at least eight characters and include a combination of at least three of the following types of characters:

▪ capital letters

▪ lower case letters

▪ numeric characters

▪ special characters (!@#$%^&*()_+|~-=\`{}[]:";'<>?,./)

f. Compound Management

i. The Contractor shall design, develop, implement and maintain a compound repository for all compounds synthesized and/or procured under this contract. The compound repository must have sufficient capacity to accommodate the anticipated workload for this contract. Solid samples must be maintained for every compound.

The Contractor must be ready within 30 days of commencing this Contract to transfer compounds from the incumbent’s repository and update the NIH database with new compound storage information if required. The Contractor shall provide determinations of compound identity, purity and stability, for all new compounds under this Contract and existing compounds as requested by the COR. The Contractor shall package and ship compounds in powder, liquid or solution form on a predetermined schedule suitable for the Contributor’s needs. The Contractor shall manage the compound inventory and track compound distribution, and update the database provided by the NIH. The Contractor shall provide certificate of analyses and protocols to the Contributor for compound handling, storage, and dilution in the Contributor’s laboratory.

g. Compound Collection

i. All compounds purchased or synthesized under this contract will be considered

Government property. The Contractor shall relocate/dispose of the collection of all compounds generated under the contract, as specified by the COR at the end of individual projects if required or as specified in the Contract Transition Plan.

h. Conduct Teleconferences and Meetings for:

i. Pre-TORFP Meeting: to review the task order requirements, timelines, milestones and deliverables; discuss task order plans and approaches and identify any anticipated difficulties in completing the task order requirements;

ii. Standing and/or ad hoc teleconferences/webinars: as requested by the COR, participate in teleconferences or webinars to review progress and performance, discuss modifications to procedures, and/or discuss other issues related to project management or infrastructure of the overall contract or individual projects;

iii. Annual Site Visits: Host an annual site visit (one day) for the COR, the Contracting Officer (CO) and other NIH staff and NIH hired consultants as requested by the COR;

iv. Ad hoc Site Visits: Host a one day meeting as requested by COR and/or CO;

v. Prepare minutes of all site visits and teleconferences/webinars and submit to the

COR for review and approval within 2 business days of the meetings.

i. Establish Confidentiality Agreements and Intellectual Property documents with Contributors to prepare for technology transfer required to bid on TORFP’s under Performance Area 2.

4.2 Performance Area 2: Medicinal Chemistry Support

NOTE: NINDS will issue TORFPs for individual projects related to the discovery and development of preclinical candidates under Performance Area 2. Performance Area 2 activities are defined below and are to be considered general Technical Requirements that will be executed following issuance of individual Performance Area 2 Task Orders. Each individual Performance Area 2 Task Order will also mailto:!@#$%^&*()_+|~-=/`{}[]:";'<>?,./) define specific and additional Technical Requirements as appropriate to that Task Order Statement of Work.

4.2.1 Overview

Under this Performance Area 2, independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the following work/services.

Medicinal Chemistry Planning, Synthesis, Isolation, Characterization

1) Project planning

2) Project management

3) Design, procurement, and milligram-scale synthesis of chemical analogs

4) Multi-gram and scale-up synthesis for testing in animal models

5) In vitro ADME and toxicology testing for lead optimization

6) Compound registration and data entry

7) Communication (teleconferences, minutes, written updates)

1. Project Planning

The NIH will issue TORFP’s to conduct a project in Performance Area 2 which will include a package of confidential information about the Contributor’s starting compounds and bioactivity assay(s) to the Contractor.

Upon receiving this introductory package, a pre-proposal teleconference may be conducted with the COR to review the introductory package and to provide the Contractor an opportunity to ask questions, if needed.

The COR may include the NIH Project Manager, NIH hired medicinal chemistry consultant(s) and NIH Contributor on this call if needed. The Contractor shall then develop a proposal for that project.

It is anticipated that all TORFP proposal responses shall include: (1) a task cost estimate; (2) a summary of any major potential IP and/or technical barriers to working with the starting compound(s), based on a brief review of recent publications and patents on the starting compound(s) and substructures in SciFinder or comparable databases (this should not be a comprehensive “freedom to operate” analysis); (3) a strategy for assessing SAR and the Contributor’s bioactivity assays, including plans to address any major IP and/or technical barriers identified, a list of in vitro ADMET assays to be conducted (if requested), and a specific list of compounds to be purchased and/or synthesized by the Contractor; (4) a staffing plan; and (5) a timeline, including schedules for exchanging materials and data and discussions among the Contributor, Contractor, and COR. The COR and/or the NIH hired consultant and the Contributor may also provide input on the SAR strategy at proposal development stage.

NINDS program staff will perform a technical review of proposals, and award selection will be made after conduct of negotiations and receipt of final proposal revisions.

2. Project Management

The Contractor shall be responsible for managing and coordinating all aspects of this contract, including the chemistry, computational support, in vitro ADMET, and compound management and logistics. The Contractor shall ensure that projects remain on schedule and the COR remains updated on all active TO’s progress.

The contractor shall ensure the project(s) is/are maintained within budget and the COR and CO are informed of any predicted overruns in advance as required.

3. Design, Procurement, and Milligram-Scale Synthesis of Chemical Analogs

The Contractor is responsible for the successful improvement of compound activity through creative intellectual input into analog molecule design, as well as the design and execution of synthetic strategies. The Contractor should obtain input on the medicinal chemistry strategy from NINDS COR, NIH Contributors and NIH external consultants.

Testing of analog compounds in in vitro assays will require milligram quantities of the compound. The Contractor shall procure desired analog compounds that are commercially available and synthesize analogs that are not. All analog compounds procured or synthesized for the purposes of in vitro testing must be at least 95% pure (unless otherwise specifically approved by the COR).

The design and/or synthesis of analog compounds could result in intellectual property. Policies regarding intellectual property are detailed in HHSAR 352.227-11 Patent Rights—Exceptional Circumstances (Sept.

2014) and summarized below (see Intellectual Property).

4. Multi-gram and Scale-Up Synthesis for Testing in Animal Models

As needed during Hit-to-Lead and Lead Optimization stages, at the request of the Government, the Contractor shall provide the Contributor with multi-gram quantities (up to 25 g) of non-Good Manufacturing Practice (non-GMP)-grade compound for select molecules. The compound must be suitable for small animal efficacy and pharmacology experiments (typically ≥98% purity), which will be performed outside of this contract.

As needed during Lead Optimization, at the request of the Government, the Contractor shall provide the Contributor with quantities of non-GMP-grade compound for select molecules. The compound amounts will typically range from 25-250g and must be suitable for large animal efficacy, pharmacology and non-GLP toxicology experiments (typically ≥98% purity), these animal studies will be performed outside of this contract.

Multi-gram or scale-up synthesis of analog compounds could result in intellectual property. Policies regarding intellectual property are detailed in HHSAR 352.227-11 Patent Rights—Exceptional Circumstances (Sept.

2014) and summarized below (see Intellectual Property).

5. In Vitro ADMET and Toxicology Testing for Lead Optimization

The Contractor shall provide a full range of in vitro assays and in vitro assay panels to investigate the SAR around pharmacological and ADMET properties. (These assays and assay panels are not for the purposes of IND-enabling studies, which are beyond the scope of this contract.) Assay panels and individual assays must be in routine use and currently operational at the Contractor’s site. The Contractor must also provide the necessary analytic method development to support these assays. To support drug discovery programs at exploratory, hit-to-lead, and lead optimization phases, the ADMET assays routinely expected are summarized in Table 4 below. The majority of the ADMET assays are expected to be conducted at the Contractor’s facility and those not conducted at the Contractor’s facilities should be noted in proposals to NIH. The in vitro toxicity experiments are expected to be employed less frequently and likely be sub-contracted to specialty CRO’s.

Proposed assay panels should encompass a sufficient range to predict the span of known pharmacological and ADMET activities.

6. Compound Registration and Data Entry

The Contractor shall be responsible for entering all data generated under the contract, including chemical structures, physicochemical and analytical purity data, and in vitro ADMET data into a database to be provided and maintained by the NIH. The Contractor shall also use this database to manage its compound inventory and track compound distribution for projects funded under this contract (see next section).

Additionally, the Contractor will upload report files in suitable format to the database and/or file sharing services (e.g. secure SharePoint site). The Contractor shall adhere to and fully comply with the Federal Information Security Management Act requirements, Public Law 107-347 (December 2002), as specified in Section H of this contract.

7. Communication

The Contractor shall participate in conference calls with each team comprised of the Contributor, NIH staff, NIH hired consultants and COR on a routine basis (typically biweekly, after each round or two of analog synthesis and testing) to present progress, review data, discuss next steps and provide minutes for these meetings for the NIH team. The Contractor shall prepare all necessary reports (see Reporting). The Contractor’s principal investigator and/or individual project leader may be asked to provide updates on ongoing projects at MCSP Executive Oversight Committee meetings and conference calls. The Executive Oversight Committee meets typically twice a year to review project team progress toward milestone progression. As required by the Contributor, the Contractor will provide written experimentals and other support to facilitate patent filings.

4.2.2 Stage Specific Scientific Task Order Requirements

4.2.2.1 Exploratory Chemistry

The goal of Exploratory Chemistry is to gather sufficient data to determine whether the starting compound(s) and primary bioactivity assay provided by the Contributor are suitable for pursuing Hit-to-Lead Chemistry. In order to initiate a Hit-to-Lead effort, compound(s) typically should elicit a reproducible dose response, demonstrate a potency of IC50/EC50 < 10 M (preferably < 1 M) with at least 10x selectivity in counterscreens, demonstrate an emerging structure-function relationship (SAR) across related chemical analogs, and provide a tractable starting point for optimization. It is expected that each Exploratory Chemistry Task Order will have a duration of approximately 6-8 months. An Exploratory task order may request any component or combinations of components centered on synthesis, Computer Aided Drug Design (CADD), in vitro ADMET support depending on the Contributors starting point and internal capabilities.

Synthetic Chemistry Support for Exploratory Chemistry Task Orders

The contractor will utilize an appropriate number of chemists to meet the projects goals and budget. It is expected that the number of chemists at the Exploratory Stage be 2-2.5 bench chemists and appropriate management, supplies, reagents, and logistical support.

Computational Chemistry/CADD Requirements for Exploratory Chemistry Task Orders:

The contractor will use their computational chemistry resources to provide guidance as requested and appropriate for Exploratory Chemistry Task Orders. The Contractor may obtain commercially available compounds that are structurally similar to the starting compound(s) (“SAR by catalog”). The Contractor, in conjunction with the Contributor and NIH hired consultants, will be responsible for identifying commercially available compounds as appropriate for purchase. To identify compounds for purchase, the Contractor will apply a battery of different search techniques to explore the SAR around hits. The contractor’s source collection of commercial compounds will be used. Besides substructure searching, the contractor should provide systems that allow the performance rapid searching of large lists of compounds. The contractor should have the ability to store all atom-pair descriptors in a searchable format so that these searches can be done with full pairwise comparisons. Additionally, the Contractor should have capability to calculate physical properties and descriptors and maintain them for all the molecules so that various lead-like, drug-like and customized filters can be readily applied. Additionally, the Contractor should provide virtual screening using docking if a suitable 3D structure of a protein is available. Any purchased compounds will be shipped weekly to the Contributor for bio-evaluation. For budget planning purposes, it is estimated that 50-100 compounds will be purchased per exploratory project.

Particular attention will be paid to properties and descriptors relevant to central nervous system (CNS) penetration. Commercial software may be utilized for the calculation of physical properties and descriptors.

Parameters most relevant to oral bioavailability and CNS penetration are predicted qualitative human absorption, predicted permeability, PSA (polar surface area), clogP (predicted partition coefficient), cLogBB (predicted penetration of the blood brain barrier) and clogS (predicted aqueous solubility).

The contractor should be able to perform pharmacophore searches, perform docking experiments on crystal structures and/or homology models as appropriate. In this way, the Contractor can approach hit exploration through any combination of 2-dimensional (2D), 3-dimensional (3D) and structure-based searches coupled with flexible property filtering to provide rapid turn-around on searches.

ADMET Requirements for Exploratory Chemistry Task Orders:

Working with the Lead Development Team (LDT), the Contractor will develop a preliminary ADMET profile to identify potential ADMET liabilities to be addressed during Hit-to-Lead Chemistry and Lead Optimization and enter data generated into the NIH database. At the onset of each exploratory ADMET study, a work plan with defined goals and decision points will be developed. The work plan will be designed to allow for rational decisions to be made concerning the viability of a hit series and approved by the COR in consultation the LDT. See Table 4 below for outline of assays by stage.

General requirements of Exploratory Chemistry Task Orders:

The Contractor, the Contributor, and COR shall communicate on a regular basis over the course of an Exploratory Chemistry project to review data and refine the testing strategy as described above. It is recognized that the resource requirements both in terms of staffing and timing may vary from program to program.

The Contractor shall procure and provide each Contributor with samples for testing in their bioactivity assay(s). The Contractor shall be responsible for maintaining a repository of the compounds synthesized or purchased by the Contractor for each of the Contributor’s projects. The Contributor shall be responsible for testing the commercial and custom-designed analogs in his or her bioactivity assay(s) and entering the bioactivity data into an NIH database that will be accessible to the Contractor.

The Exploratory phase of a project will end when the COR determines that sufficient data is available to make a decision on whether to proceed with Hit-to-Lead Chemistry.

4.2.2.2 Hit-to-Lead Chemistry

Efforts on a hit series advanced from the Exploratory Chemistry stage or entering directly into to the Hit-To- Lead stage will be focused on development of a clear understanding of the SAR as well as the Structure- Property Relationships (SPR) within the hit series, demonstration of favorable outcomes for preliminary ADMET and increased potency in the Contributor’s primary assay as well as demonstrated potency in a cellular assay. For each program, a target profile will be established, addressing bioactivity, ADMET liabilities and drug-like properties which will serve as decision points and advancement criteria. Typical advancement criteria with respect to bioactivity in the Contributor’s assays are illustrated in Table 1. Specific bioactivity advancement criteria will be program dependent.

Table 1. Bioactivity Advancement Criteria

Assay Advancement Criteria

Primary Bioassay IC50 or EC50 < 100 nM

Cellular Assay IC50 or EC50 < 100 nM

Selectivity Assays No Significant Issues (e.g. 100x)

For budgeting purposes, it is expected that each Hit-to-Lead project will have a duration of approximately twelve (12) months.

Synthetic Chemistry Support for Hit-to-Lead Task Orders:

The Contractor will utilize an appropriate number of chemists to meet the projects goals and budget. It is expected that the number of chemists at the Hit-to-Lead Stage will be 4 bench chemists and appropriate management and logistical support. Projects in Hit-to-Lead Chemistry will involve iterative rounds of analog synthesis and testing, typically on a weekly or biweekly schedule. For each round, the Contractor, the Contributor, COR, and the NIH consultants will review the most recent data and discuss the next set of analogs to generate.

Computational Chemistry/CADD Requirements for Hit-to-Lead Task Orders:

In order to assist in analog design, the Contractor’s Computational Chemistry/CADD group will establish a list of proposed synthesis targets, providing for the calculation of relevant ADMET parameters that will provide support in targeting the preparation of analogs with drug-like properties, favoring penetration of the CNS.

Early in the Hit-to-Lead process, the Contractor may use various cheminformatic tools to group targeted compounds according to scaffold and calculated properties and permit the team to predict and evaluate possible series of molecules according to their potential liabilities and to plan approaches to improve activity within a series. If a crystal structure of the protein target is available or if a good homology model can be made, then the Contractor may apply automated docking tools to the hit compounds and the modeled structures can be evaluated for areas of opportunity to improve properties and activity within a series. When protein structures are not available, then 3D alignments and pharmacophore models may be constructed which can be helpful in the organization and planning of the medicinal chemistry strategy.

ADMET Requirements for Hit-to-Lead Task Order:

During Hit-to-Lead Chemistry, it may be necessary to address a specific pharmacological or toxicological liability. In these cases, the Contractor will be responsible for providing appropriate in vitro testing for this purpose and entering the data into an NIH database. Preliminary ADMET for compounds to advance to the Lead Optimization stage should be favorable. The Contractor should provide a large variety of in vitro assays that can be carried out efficiently in a high-throughput mode for large sets of compounds – quickly identifying the primary ADMET characteristics of compounds. Some of the assays that are typically included in preliminary testing panels to complement the hit-to-lead chemistry efforts in an iterative strategy are listed in Table 2 along with desired outcomes.

Table 2. ADMET Criteria

Assay Desirable Range

Aqueous Solubility >10 M

Microsome Stability >50% remaining @ 1 h

CYP Inhibition <50% at 10 M

Plasma protein Binding < 90%

MDCK-MDR1 Papp>3x10e-6 cm/s and Efflux ration <3

- Aqueous Solubility: various models for both kinetic and thermodynamic solubility in a variety of test environments should be available. These will be prioritized as appropriate for interpreting biological assays, and/or for addressing bioavailability issues under appropriate physiological conditions for a given formulation and delivery route.

- Metabolic Stability, Plasma Stability, and/or Chemical Stability to evaluate drug half-life and clearance in the presence of primary metabolizing enzymes and environments based on route of administration.

Assays should be conducted using liver microsomes, liver S9 fractions, hepatocytes, simulated digestive fluids, as well as…