RFP_No._NIHDA-2018-00198_(Signed).pdf

National Institute on Drug Abuse Request for Proposal (RFP) No. NIHDA-2018-00198

“Assessment of Potential Substance Abuse Treatment Medications in Nonhuman Primate Models”

Issued by:

Andrew Hotaling, Contracting Officer NIDA Section, Contracts Management Branch Blue Office of Acquisition, NIDA National Institute on Drug Abuse, NIH 6001 Executive Boulevard Room 4211, MSC 9559 Bethesda, MD 20892-9559

Point of Contact: Tracy Cain, Contracting Officer E-Mail: tracy.cain@nih.gov Phone: 301.443.6677

DATE ISSUED: Tuesday, August 28, 2018

PROPOSAL DUE DATE: Friday, September 28, 2018, 2:00 P.M. Eastern Time

The National Institute on Drug Abuse invites you to submit a proposal responding to the requirements of this RFP No. NIHDA-2018-00198 titled “Assessment of Potential Substance Abuse Treatment Medications in Nonhuman Primate Models”.

This RFP is prepared in accordance with the Uniform Contract Format (UCF) prescribed for Government wide application by the Federal Acquisition Regulation (FAR). The UCF is both an RFP and contract award document. The resulting contract will consist of Parts I, II, III of the Uniform Contract Format.

We expect to award a cost reimbursement level of effort-type contract for a base period of 1 year with potential for four 1-year option years and additional option quantities. We will fund options dependent on the previous year's performance and the availability of funds. Please anticipate that the base performance period of the contract will be from December 16, 2018 to December 15, 2019. You must respond with technical and pricing proposals for the entire project and total period of performance, including separately priced option years and option quantities.

General

Part IV of the RFP contains instructions, provisions, and evaluation factors for the submission and review of proposals. Attachment 2 is a "Proposal Intent Response Sheet." Please complete this form and return it to tracy.cain@nih.gov by September 11, 2018. The balance of Parts I, II, and III contain provisions, clauses, and special requirements which will be made a part of any resultant award. Please review these sections and consider their impact on performance, mailto:tracy.cain@nih.gov mailto:tracy.cain@nih.gov capability, technical, and cost factors as you develop your proposal. Do not fill in blanks or otherwise complete portions of Parts I, II, and III which appear to require additional information.

The Government will complete these items prior to contract award and, if negotiations are conducted, will tailor those items through final negotiations.

Furnish in writing (e-mail is acceptable) to the Contracting Officer any areas of uncertainty, which, in your opinion, require clarification or correction. You must submit your questions in sufficient time for receipt by the Contracting Officer on or before September 11, 2018. Mark the e-mail, "Offeror's Questions, RFP No. NIHDA-2018-00198."

The Business Proposal

The Business Proposal must contain a detailed breakdown of costs by task, for each cost category/element, an explanation of the basis for all costs, and provide documentation to support these costs. Please utilize the Breakdown of Proposed Estimated Costs and Excel spreadsheet contained in Attachment 10.

A completed Form NIH-2043, “Proposal Summary and Data Record” must be included with the Business Proposal. Include the e-mail addresses of both the Principal Investigator and the responsible business representative on the form.

The Offeror must submit its Travel Policy, Total Compensation Plan and Annual Report with the initial Business Proposal.

See Section L.2.c. for additional detail.

The Technical Proposal

Offerors shall complete and attach the “Technical Proposal Cover Sheet” to their technical proposal. Be sure to list all professional personnel and organizations named in the proposal who have any role in the proposed work including staff, subcontractors, collaborating organizations, and consultants. Organizational affiliation(s) must be shown for each person named. If needed, additional sheets may be included using the same format. This information is vital to ensure that no conflicts of interest exist with the review committee members.

Format and content requirements for the Technical Proposal are detailed in Section L.2.b.

Submitting a Proposal

Proposals must be submitted via the electronic Contract Proposal Submission (eCPS) website (https://ecps.nih.gov) no later than Friday, September 28, 2018, 2:00 P.M. Eastern Time.

Proposals submitted by facsimile, e-mail, or hard copy will not be accepted. An official authorized to bind your organization must sign the proposal.

Offerors are solely responsible for submitting proposals in a timely manner. Please note that creating an account to submit may take up to three (3) business days. Please plan accordingly. Additional instructions on how to submit a proposal via eCPS can be found http://rcb.cancer.gov/rcb-internet/forms/2043.pdf http://ocm.od.nih.gov/contracts/rfps/TechCov.htm https://ecps.nih.gov/ at https://ecps.nih.gov/home/howto and in Attachment 01.

All notices related to this solicitation will be posted on FedBizOpps (https://www.fbo.gov) as well as the NIDA Contracts Home Page (https://www.drugabuse.gov/funding/funding-opportunities/nida-requests-contract-proposals-rfps). If you would like to receive e-mail notifications of updates to this solicitation, please register with FedBizOpps.

In accordance with FAR 15.306(a)(3) and FAR 52.215-1, the Government intends to evaluate proposals and award a contract without discussions. Therefore, your initial proposal should contain the best terms from cost or price and technical standpoints. The Government does, however, reserve the right to conduct discussions if the Contracting Officer determines them to be necessary.

Disclaimers

This RFP does not commit the Government to pay the costs for the preparation and submission of a proposal. The Contracting Officer is the only individual who legally can commit the Government to the expenditure of public funds in connection with this acquisition.

Any contract award for this requirement is contingent on the availability of funds (see FAR 52.232-18, Availability of Funds – April 1984).

The National Institute on Drug Abuse appreciates your interest in this RFP and looks forward to receipt of your proposal. Requests for any information concerning this RFP should be directed to Tracy Cain, at the NIDA Section, Contracts Management Branch Blue, who may be reached at (301) 443-6677; collect calls will not be accepted. Discussions with any other individual outside the NIDA Section, Contracts Management Branch Blue should not occur.

Sincerely, Andrew Hotaling, Contracting Officer NIDA Section, Contracts Management Branch Blue Office of Acquisition, NIDA/NIH

Enclosure https://ecps.nih.gov/home/howto https://www.fbo.gov/ https://www.drugabuse.gov/funding/funding-opportunities/nida-requests-contract-proposals-rfps https://www.drugabuse.gov/funding/funding-opportunities/nida-requests-contract-proposals-rfps

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SOLICITATION

SECTION A - SOLICITATION/CONTRACT FORM

1. Requisition or other Purchase Authority: P.L. 102-321

2. Request for Proposal (RFP) Number:

NIHDA-2018-00198

3. Issue Date:

08/28/2018

4. Set Aside:

[X] No

[ ] Yes See Part IV Section L

5. Title : Assessment of Potential Substance Abuse Treatment Medications in Nonhuman Primate Models

6. ISSUED BY:

NIDA Section Contracts Management Branch Blue, Office of Acquisition National Institute on Drug Abuse, National Institutes of Health 6001 Executive Blvd, Ste 4211 MSC 9559 Bethesda, Maryland 20892-9559* If delivering by other than USPS, change the city and zip code to Rockville, MD 20852

7. SUBMIT OFFERS TO:

See Part III, Section J, "Packaging and Delivery of the Proposal," ATTACHMENT 1 of this Solicitation.

8. Proposals for furnishing the supplies and/or services in THE SCHEDULE will be received at the place specified in, and in the number of copies specified in Attachment 1, "Packaging and Delivery of the Proposal," until 2:00 PM local time on September 28, 2018. Offers will be valid for 120 days unless a different period is specified by the offeror on the Attachment entitled, "Proposal Summary and Data Record, NIH 2043.

9. This solicitation requires delivery of proposals as stated in ATTACHMENT 1, "Packaging and Delivery of the Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website." If proposals are required to be delivered to two different locations, the OFFICIAL POINT OF RECEIPT for determining TIMELY DELIVERY is the eCPS Website.

IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR HIS DESIGNEE

AT THE PLACE AND TIME SPECIFIED FOR THE OFFICE OF ACQUISITIONS, THEN IT WILL BE

CONSIDERED LATE AND HANDLED IN ACCORDANCE WITH subparagraph (c)(3) of FAR Clause 52.215-1, Instructions to Offerors--Competitive Acquisition," LOCATED IN SECTION L.1. OF THIS

SOLICITATION.

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

11. FOR INFORMATION CALL: Tracy Cain, Contracting Officer PHONE: 301-443-6677 e-MAIL: tracy.cain@nih.gov

COLLECT CALLS WILL NOT BE ACCEPTED.

Andrew Hotaling, Contracting Officer NIDA Section Contracts Management Branch Blue, Office of Acquisition, NIDA http://www.sam.gov

RFP Number : NIHDA-2018-00198

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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

PART III - LIST OF DOCUMENTS, EXHIBITS AND OTHER ATTACHMENTS

SECTION J - LIST OF ATTACHMENTS

SOLICITATION ATTACHMENTS

TECHNICAL PROPOSAL ATTACHMENTS

BUSINESS PROPOSAL ATTACHMENTS

INFORMATIONAL 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. LEVEL OF EFFORT

e. COMMITMENT OF PUBLIC FUNDS

f. COMMUNICATIONS PRIOR TO CONTRACT AWARD

g. RELEASE OF INFORMATION

h. PREPARATION COSTS

i. SERVICE OF PROTEST

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. Standards for Privacy of Individually Identifiable Health Information

10. Privacy Act - Treatment of Proposal Information

11. Selection of Offerors

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12. Institutional Responsibility Regarding Investigator Conflicts of Interest

13. ROTC Access and Federal Military Recruiting on Campus

14. Certification of Filing and Payment of Taxes

15. Past Performance Information

16. Electronic Information Technology Accessibility Notice, HHSAR 352.239-73 (December 2015)

17. Solicitation Provisions Incorporated by Reference

b. TECHNICAL PROPOSAL INSTRUCTIONS

1. Technical Discussions

2. Other Considerations

3. Technical Evaluation

4. Care of Live Vertebrate Animals

5. Research Involving Live Vertebrate Animals

6. Obtaining and Disseminating Biomedical Research Resources

c. BUSINESS PROPOSAL INSTRUCTIONS

1. Basic Cost/Price Information

2. Proposal Cover Sheet

3. Information Other than Cost or Pricing Data

4. Requirements for Cost or Pricing Data or Information Other than Cost and Pricing Data

5. Salary Rate Limitation

6. Small Business Subcontracting Plan

7. Mentor Protege Program, HHSAR 352.219-70

8. HUBZone Small Business Concerns

9. Total Compensation Plan

10. Other Administrative Data

11. Qualifications of the Offeror

12. Subcontractors

13. Proposer's Annual Financial Report

14. Travel Costs/Travel Policy

SECTION M - EVALUATION FACTORS FOR AWARD

1. GENERAL

2. COST/PRICE EVALUATION

3. LIVE VERTEBRATE ANIMALS EVALUATION

4. MANDATORY QUALIFICATION CRITERIA

5. EVALUATION OF OPTIONS

6. EVALUATION OF DATA SHARING PLAN

7. TECHNICAL EVALUATION FACTORS

8. PAST PERFORMANCE FACTOR

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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 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 PROVISIONS 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 IF NECESSARY AND WILL BE INCLUDED IN THE RESULTANT CONTRACT. THE ENCLOSED CONTRACT SCHEDULE IS INTENDED TO PROVIDE THE OFFEROR WITH THE NECESSARY INFORMATION

TO UNDERSTAND THE TERMS AND CONDITIONS OF THE RESULTANT CONTRACT.

SECTION B - SUPPLIES OR SERVICES AND PRICES/COSTS

ARTICLE B.1. BRIEF DESCRIPTION OF SUPPLIES OR SERVICES

The objectives of this contract are to determine the effects of compounds in the following paradigms: (1) drug discrimination test in nonhuman primates when tested alone or in combination with cocaine or other drugs of abuse and (2) self-administration test in nonhuman primates when tested for ability to reduce cocaine (or other drugs of abuse) self-administration or to be directly self-administered.

ARTICLE B.2. ESTIMATED COST - OPTION

a. The estimated cost of the Base Period of this contract is $ .

b. The fixed fee for the Base Period of this contract is $ . The fixed fee shall be paid in direct ratio to the level of effort expended; that is, the percent of fee paid shall be equal to the percent of total effort expended.

Payment shall be subject to the withholding provisions of the clauses ALLOWABLE COST AND PAYMENT and FIXED FEE referenced in the General Clause Listing in Part II, ARTICLE I.1. of this contract.

c. The total estimated amount of the contract, represented by the sum of the estimated cost plus the fixed fee for the Base Period is $ .

d. If the Government exercises its option pursuant to the OPTION PROVISION Article in SECTION H of this contract, the Government's total estimated contract amount represented by the sum of the estimated cost plus the fixed fee will be increased as follows:

Estimated Cost ($) Fixed Fee ($) Estimated Cost Plus Fixed Fee ($)

Base Period Option Period 1 Option Period 2 Option Period 3 Option Period 4 Total

[Base Period and Option(s)]

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e. If the Government exercisies any of its option quantites pursuant to the OPTION PROVISION Article in SECTION H of this contract, the Government's total estimated contract amount represented by the sum of the estimated cost plus the fixed fee will be increased as follows:

Estimated Cost ($) Fixed Fee ($) Estimated Cost Plus Fixed Fee ($)

Option Quantity 1 Option Quantity 2 Option Quantity 3 Option Quantity 4 Option Quantity 5 Option Quantity 6 Total Option Quantities:

f.

Ultimate Contract Value (Base Period, Option Periods, and Option Quantities):

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. NIDA reserves the right to have the contracted services in this contract benefit NIDA and other components of NIH.

[Remainder of Page Intentionally Left Blank]

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SECTION C - DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

ARTICLE C.1. STATEMENT OF WORK

a. I. Introduction/Objectives

The objectives of this contract are to determine the effects of compounds in the following paradigms: (1) drug discrimination test in nonhuman primates when tested alone or in combination with cocaine and (2) self-administration test in nonhuman primates when tested for ability to reduce cocaine self-administration or to be directly self-administered.

Insofar as the Addiction Treatment Discovery Program (ATDP) is a screening and evaluation program that utilizes standardized protocols, the Contractor shall be willing to adopt the ATDP protocols in order to accommodate the needs of the program. However, NIDA recognizes that advances in the field of substance abuse research during the course of the Contract may require modification of the testing paradigms as specified in the Statement of Work. In addition, shifting priorities within NIDA may require this contract to support testing needs using other drugs of abuse, particularly opioids. If necessary, the Contracting Officer will issue a modification requiring introduction of these tests into the testing program, and appropriate options will be exercised to cover the cost. These options will cover animal purchases, laboratory supplies, and labor.

The NIDA Division of Therapeutics and Medical Consequences anticipates that, based on promising findings in preliminary rodent studies and nonhuman primate studies, some potential treatment medications will require additional follow-up preclinical studies in nonhuman primates. These follow-up studies may be required so that the Addiction Treatment Discovery Program can decide whether to recommend these compounds as drug development candidates. NIDA cannot accurately predict the need for these follow-up studies and the precise experimental design of the studies will depend upon initial findings. In part to address this uncertainty, options are included in this Statement of Work that may cover the labor hours for these studies. Separate options are included to cover purchases and laboratory supplies.

II. Services to be Performed

A. General Requirements

1. Independently, and not as an agent of the Government, the Contractor shall furnish all necessary labor, materials, supplies, equipment, and services (except as otherwise specified herein) and perform the work set forth below.

2. All work under this contract shall be monitored by the Government Contracting Officer's Representative (COR).

B. Specific Requirements

1. Task Requirements

Task 1: The specific objectives of this task are to determine the efficacy (i.e., dose response evaluation) of ATDP compounds to substitute for the discriminative stimulus effects of cocaine and/or to inhibit or antagonize the discriminative stimulus effects of a cocaine injection. Within Task 1, the Contractor shall conduct two distinct experimental procedures referred to as the substitution protocol and the antagonism protocol. The Contractor shall conduct both of these protocols in monkeys trained to discriminate cocaine from saline according to the procedures and experimental specifications described in Subsection C. For Task 1, the Contractor shall utilize a maximum of eight monkeys and a minimum of three monkeys for each compound evaluation. At the time of award, all monkeys used for Task 1 shall be male rhesus monkeys (Macaca mulatta); however, over the life of the contract, if it becomes increasingly difficult for the Contractor to obtain virus-free rhesus monkeys, the NIDA Contracting Officer's Representative (COR) may authorize the use of a different type of monkey (e.g., cynomolgous

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Macaca fascicularis monkeys). The Contractor shall perform all testing on compounds assigned by the COR. The Contractor shall blind the identity of all standard compounds under evaluation to those conducting the assays. Any alterations in the described protocol design and conduct are subject to COR approval. Approximately 5-12 compounds will be evaluated each contract year.

Task 2: The specific objectives of this task are to determine the efficacy (i.e., dose response evaluation) of ATDP test compounds to alter cocaine-maintained responding (i.e., cocaine self-administration) as compared to food-maintained responding in nonhuman primates (pretreatment protocol), and/or to evaluate the efficacy of ATDP compounds to replace cocaine as the drug available for intravenous self-administration (substitution protocol). The pretreatment self-administration protocol shall be conducted by the Contractor according to the specifications described in Subsection D, and requires that the efficacy of ATDP compounds be evaluated at multiple (i.e., more than 2) doses, sufficient to characterize compound-induced alterations (shifts) in the cocaine dose-response curve. Likewise, the Contractor shall conduct the substitution self-administration protocol according to the specifications described in Subsection D and requires that the Contractor evaluate test compounds at multiple unit doses. Both of these protocols shall be conducted by the Contractor in male rhesus monkeys (Macaca mulatta) trained to self-administer food and cocaine (intravenous (i.v.) injection method) according to the training procedures and experimental specifications described in Subsection D. For Task 2, the Contractor shall utilize a minimum of eight monkeys with a minimum of four monkeys utilized for each compound evaluation. At the time of award, all monkeys used for Task 1 shall be male rhesus monkeys (Macaca mulatto); however, over the life of the contract, if it becomes increasingly difficult for the Contractor to obtain virus-free rhesus monkeys, the NIDA COR may authorize the use of a different type of monkey (e.g., cynomolgous Macaca fascicularis monkeys). The Contractor shall perform all testing on compounds assigned by the COR. The Contractor shall blind the identity of all standard compounds under evaluation to those conducting the assays. Any alterations in the described protocol design and conduct are subject to approval by the COR. The Contractor shall evaluate approximately 5-12 compounds.

Task 3: Approximately every 12 months (if options are exercised), the Contractor shall attend a meeting (up to 2 days each) with NIDA staff and possibly a group of consultants for the purpose of reviewing past, current and/or proposed work under this contract. Specific items for discussion will be subject to the approval of the NIDA COR. Prior to each meeting, the Contractor shall, if requested by the NIDA COR, prepare "pre-meeting packets" summarizing all data on test compounds to be presented and describing relevant protocol methods. The Contractor shall include summaries of: proposals for optimization of existing protocols;

progress in ongoing protocol development (Task 6, Task 7); proposals for new protocol development; problems encountered in the implementation of tasks required by the contract;

and proposed solutions to problems encountered. The Contractor shall send this information to the NIDA COR at least three weeks in advance of each meeting for approval, and after approval is obtained, to each consultant at least two weeks prior to the meeting. The Contractor shall present this information at the meetings and subsequently prepare a report to summarize and synthesize the findings of each meeting. In most cases, the site of the meetings shall be in the Washington, D.C. area. However, in some special circumstances the NIDA COR may designate another meeting site, such as a professional meeting (e.g., College on Problems of Drug Dependence meeting, Society for Neuroscience meeting, etc.).

This contract shall be responsible for payment of the Contractor's travel expenses (up to three persons) to all contract and/or consultant meetings. Another NIDA contract will pay all expenses for the consultants. The NIDA COR may specify which individuals will serve as consultants.

Task 4: The Contractor shall maintain a chronological list of compound authorization, receipt, usage, and evaluation. The Contractor shall maintain separate logs for compounds authorized for drug discrimination and self-administration testing. The following information shall be recorded in tabular form: (1) compound under study (the ATDP compound number with

- 8 -associated batch number or compound name if provided), (2) date when written authorization to evaluate a compound was obtained from the COR, (3) description of authorized protocol procedure (i.e., drug discrimination or self-administration utilizing substitution, antagonism or pretreatment protocol), (4) date when compound was received from distribution site, (5) date of study initiation (date that laboratory testing begins), (6) study completion date (date when Contractor deems laboratory testing to be complete), (7) date that resulting Final Study Report was sent to the NIDA COR, and (8) date of report revision, if requested. The Contractor shall maintain this table chronologically, by date of compound testing authorization. The Contractor shall update this table at least once each month, within 5 working days before the submission date of each Monthly Progress Report.

Task 5: The Contractor shall retain, for the duration of this contract, all laboratory notebooks (which shall include hard copies of raw data) and any electronic data files generated under this contract, as well as all coded ATDP compounds received for evaluation under this contract.

Beginning on a date specified by the NIDA COR and continuing throughout the life of the contract, the Contractor shall maintain a cumulative data table in electronic spreadsheet format. The table shall contain, for each standard or test compound evaluated, all values (e.g., ED50 values) that the NIDA COR indicate will be entered into NIDA's internal medications development database in a format to be specified by the COR. The Contractor shall update the table at least monthly. Simultaneous with table updates, the Contractor shall, if so instructed by the NIDA COR, electronically transfer all new data to NIDA. The NIDA COR will provide the Contractor with appropriate instructions for transferring data. In lieu of the above, the NIDA COR may require the Contractor to submit the updated table on a data storage device such as a USB flash drive, by mail. In addition, the Contractor shall label complete electronic data files and electronic files of all study reports according to ATDP compound number and date of evaluation. On or before the expiration date of this contract, the Contractor shall ship the laboratory notebooks and electronic files to the NIDA COR. On or before the expiration date of the Contract, the Contractor shall ship the test compounds, following authorization by the COR, to the NIDA-contracted compound distribution site.

Task 6: As directed by the NIDA COR, the Contractor shall conduct follow-up studies on compounds with particular promise as clinical candidates for treatment of drug dependence.

These studies may necessitate the development and pharmacological characterization of a nonhuman primate model of drug dependence that is amenable to the evaluation of potential pharmacotherapeutic agents. Examples of such follow-up studies may include but are not limited to the following: (1) modification of the specified protocols in Subsections C and D that would allow for a more rapid evaluation of compounds and thus increase compound throughput; (2) development of a protocol that has features similar to the clinical situation of relapse to drug use; (3) development of a protocol that utilizes neuroendocrine, neurochemical and/or physiological endpoints that are relevant to drug dependence and/or withdrawal; and

(4) development of individualized, specific protocols with regard to dosing, schedule of testing, or other parameters as needed for the evaluation of particular compounds. Study designs shall be subject to the prior review and approval of the NIDA COR. Data reports and compound testing by the Contractor shall adhere to a format determined by the NIDA COR. Work under this task may or may not be authorized by the COR depending upon the needs of Program, and would require the exercise of options.

Task 7: As directed by the NIDA COR the Contractor shall develop drug discrimination and self administration protocols using an opiate compound, THC, or possibly another drug of abuse as the training drug, and conduct assessments of potential treatment medications using these methods described under Tasks 1 and 2. Although the protocols may be similar to those used for cocaine, differences in pharmacokinetics or other factors may necessitate different training procedures, operant schedules and protocol differences that cannot be specified at this time. In addition, the use of other primate species may be considered depending upon the rationale. Through the exercise of options, protocols would be developed and approved, additional animals would be obtained, trained, and used for testing. Data reports prepared by the Contractor shall adhere to a format determined by the NIDA COR. Work under this task

- 9 -may or may not be authorized by the COR depending upon the needs of Program, and would require the exercise of options.

2. Schedule of Work

Base Period plus Option Periods 1 through 4 and Option Quantities (if options are exercised):

I. The Contractor shall evaluate up to 12 compounds as described under Task 1 and evaluate up to 12 compounds as described under Task 2. The Contractor shall also conduct the work described under Tasks 3 through 5.

II. Options (available each year):

Option 1: The Contractor shall devote up to 1000 person hours to the work described under Task 6 and/or Task 7.

Option 2: The Contractor shall devote up to 2000 person hours to the work described under Task 6 and/or Task 7.

Option 3: The Contractor shall devote up to 4000 person hours to the work described under Task 6 and/or Task 7.

Option 4: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $20,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

Option 5: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $40,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

Option 6: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $60,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

C. Protocol Specifications for Task 1: Cocaine Discrimination Protocol

1. Subjects: The subjects will be six male rhesus monkeys (Macaca mulatta) weighing approximately

5.0 to 7.5 kg. The Contractor shall maintain each monkey on a diet of three to four monkey biscuits and one piece of fresh fruit per day. During the week, the Contractor shall deliver all food after the experimental session, whereas on weekends, the Contractor shall deliver food between 9 a.m. and noon. Water will be freely available for all monkeys at all times. The Contractor shall maintain the room in which the monkeys are housed on a 12-hour light/dark cycle, with lights on from 7 a.m. to 7 p.m.

The Contractor shall conduct animal maintenance and research in accordance with NIH guidelines provided by the Committee on Laboratory Animal Resources. The facility must be licensed by the United States Department of Agriculture, and protocols must be approved by the Institutional Animal Care and Use Committee. Consulting veterinarians shall periodically monitor the health of the monkeys.

Monkeys will have visual, auditory, and olfactory contact with other monkeys throughout the study.

Operant food and drug self-administration procedures will provide an opportunity for environmental manipulation and enrichment.

2. Apparatus: The Contractor shall house each monkey individually in a well-ventilated, stainless steel chamber. The Contractor shall modify home cages of all monkeys to include an operant panel mounted on the front wall. The Contractor shall arrange three square translucent response keys in a horizontal row of the operant panel. Each key should be transilluminated by red, green, or white stimulus lights.

In addition, the Contractor should design the operant panel to support an externally mounted pellet dispenser that delivers one gram of fruit-flavored food pellets to a food receptacle mounted on the cage beneath the operant response panel. The Contractor shall accomplish operation of the operant panels and data collection with appropriate computers located in a separate room.

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3. Discrimination training - general procedures: The Contractor shall run all monkeys 5 days per week during daily sessions composed of multiple cycles. Each cycle will consist of a 15-minute time-out period followed by a 5-minute response period. During the time-out, all stimulus lights will be off and responding will have no scheduled consequences. During the response period, the right and left response keys will be transilluminated red or green and monkeys can earn up to 10 food pellets by responding under a fixed ratio (FR) 30 schedule of food presentation. For two of the four monkeys, the Contractor shall illuminate the left key green and the right key red. For the remaining four monkeys, the Contractor shall reverse the colors of the response keys. The Contractor shall not illuminate the center key at any time, and responding on the center key will have no scheduled consequences.

If all ten food pellets are delivered before the end of the 5-minute response period, the stimulus lights transilluminating the response keys will be turned off and responding will have no scheduled consequences for the remainder of the 5-minute period.

On training days, the Contractor shall give the monkeys an intramuscular (i.m.) injection of either saline or 0.40 mg/kg cocaine 5-minute into each time-out period (i.e., 10 min before the response period).

Following the administration of saline, responding on only the saline-appropriate key will produce food, whereas following administration of 0.40 mg/kg cocaine; only responding on the drug-appropriate key will produce food. Responses on the inappropriate key will reset the FR requirement on the appropriate key. The Contractor shall run the monkeys for one to five cycles, and if the Contractor administers the training dose of cocaine, the Contractor shall administer it only during the last cycle. Thus, training days will consist of 0-5 saline cycles followed by 0-1 drug cycles.

4. Dependent Variables to be Measured: During each response period, three dependent variables will be determined using the following equations.

a. Percent injection-appropriate responding prior to delivery of the first reinforcer as defined by:

(Injection-appropriate responses emitted prior to 1st reinforcer / Total responses emitted prior to delivery of 1st reinforcer) X 100

b. Percent injection-appropriate responding for the entire response period as defined by:

(Injection-appropriate responses emitted during response period / Total responses emitted during response period) X 100

c. Response Rate as defined by:

(Total responses emitted during response period / Total response period time in seconds*

*Total Response Period Time = either 5 min or the time from the start of the cycle to the time when the 10th reinforcer was delivered, if all 10 FRs were completed.

5. Criteria for discrimination: Monkeys shall have acquired cocaine discrimination when the following three criteria are met for seven of eight consecutive training sessions including the most recent session.

a. The percent injection-appropriate responding prior to delivery of the first reinforcer is greater than or equal to 80% for all cycles.

b. The percent injection-appropriate responding for the entire cycle is greater than or equal to 90% for all cycles

c. Response rates during saline training cycles are greater than 1.0 responses per second.

6. Discrimination Testing:

a) General Procedure: Once monkeys meet criterion levels of cocaine discrimination, testing will begin. Test sessions will be identical to training sessions except that responding on either key produces food, and the Contractor shall administer compounds using either a substitution or a pretreatment protocol as described below. In general, the Contractor shall conduct training sessions on Mondays, Wednesdays and Thursdays, and the Contractor shall

- 11 -conduct test session on Tuesdays and Fridays. TheContractor shall run test sessions only if the three criteria listed above under "Criteria for Discrimination" are obtained during the training day immediately preceding the test day. If responding does not meet criterion levels of discrimination performance, then theContractor shall continue training until criterion levels of performance are obtained for at least 2 consecutive days.

b) Test Compound Evaluation: Test compounds will be evaluated using the substitution test protocol, the antagonism pretreatment test protocol or both as directed by the COR. Doses, pretreatment times, and routes of administration for each new medication will be chosen in consultation with the COR based on information concerning pharmacokinetics, peak effect and duration of action. The Contractor must be able to administer oral doses of test compound when specified by the COR. In general, the Contractor will use the following procedures:

(1). Substitution Protocol: In a substitution protocol, the Contractor shall administer the test compound alone using a cumulative dosing procedure. In this procedure, each monkey will receive a dose of the test compound five minutes into each cycle of a multiple cycle session. The cumulative dose equals the sum of all doses administered during that session. In a typical cumulative dosing procedure, each dose will increase the total dose by 1/4 to 1/2 log units. In general, doses of the test drug will be evaluated from those that are inactive up to doses that either: a) increase the percent drug-appropriate responding for the entire response period to greater than or equal to 90%, or b) decrease response rates to less than 0.1 responses/sec.

For each study, the Contractor shall test four monkeys.

(2). Antagonism Pretreatment Protocol: In a pretreatment protocol, the Contractor shall administer the test compound as a pretreatment at some time (usually 30 minutes) before the determination of a cumulative cocaine dose-effect curve. In general, the Contractor shall evaluate the test compound up to doses that either: a) produce a significant change in the cocaine dose-effect curve (to either the right or left), or b) decrease response rates to less than 0.1 responses/sec averaged over the entire session. For each study, the Contractor shall evaluate at least two monkeys.

For test compounds with short durations of action, it may be necessary to assess the full range of cocaine doses in two test sessions. This will ensure that the effects of the higher doses of cocaine are determined within a timeframe in which the test compound is active. In instances where a short duration of action is suspected by the Contractor, the COR will be notified and further testing instructions will be obtained. Similarly, in instances where a long duration of compound action is suspected by the Contractor, the COR will be notified and further testing instructions will be obtained. In these instances, the Contractor may conduct a supplementary test with each dose of the test compound, or conduct additional evaluations of response rate on days subsequent to compound administration.

In addition to collection of response rate measures, the Contractor shall note and systematically record observable pharmacological or toxicological effects following test compound administration for each monkey. The Contractor shall note these effects in the study report.

7. Generation of cocaine dose-effect curves: Cumulative cocaine dose-effect curves will be determined using the substitution protocol described above. Cocaine will be administered using cumulative dosing procedures in which each dose administration increases the total dose by 1/2 log unit. The Contractor shall obtain control cocaine dose-effect curves using the following cumulative dosing sequence: 0.013, 0.04, 0.13, 0.4, 1.3 mg/kg.

8. Route of administration: The Contractor shall administer all test compounds i.m. or p.o. (nasal/oral gavage) as specified by the COR unless: (1) initial injections of a test compound cause unacceptable irritation at the injection site, (2) physical characteristics (i.e., particle size or pH) clearly indicate that a solution or suspension will cause unacceptable irritation at the injection site, or (3) the NIDA COR specifically requests an alternative route of administration. In cases where irritation at the injection

- 12 -site precludes the i.m. route of administration, the Contractor shall consult the NIDA COR before proceeding to an alternative route of administration, which may require a different pretreatment time.

9. Pretreatment time: Unless otherwise requested by the NIDA COR, the Contractor shall utilize a 30-minute pretreatment time for i.m. injections and a 90-minute pretreatment time for nasal/oral gavage administration.

10. Data analysis:

a. Test compound substitution protocol: For the substitution protocol, the Contractor shall plot individual subject graphs of the percent drug-appropriate responding for the entire response period and the response rate as a function of the dose of the test compound (log scale). Test compounds shall be considered to generalize to cocaine if some dose of the test compound produces at least 90% cocaine-appropriate responding. For compounds that generalize to cocaine, the slope of the test compound dose-effect curve and the slope of the cocaine dose-effect curve will be evaluated for parallelism using standard pharmacological procedures. In addition, the Contractor shall compare the relative potency of cocaine and the test compound.

The Contractor will report ED50 values for those test compounds that generalize to cocaine.

For each test compound that substitutes partially (>10% and <90%) for cocaine, the lowest dose that produces maximum cocaine-appropriate responding will be reported, as well as the associated maximum cocaine-appropriate responding value.

b. Test compound antagonism pretreatment protocol: For the pretreatment protocol, individual subject graphs of the percent drug-appropriate responding for the entire response period and the Contractor will plot response rate as a function of cocaine dose. The Contractor will evaluate the slopes and relative potencies of the cocaine dose-effect curves determined alone and following pretreatment with various doses of the test compound as above. For each test compound that significantly alters the cocaine dose-response curve, the Contractor will report ED50 values for cocaine curves determined in the presence of active doses of test compound, as well as for the corresponding control cocaine curves.

D. Protocol Specifications for Task 2: Cocaine Self-Administration Protocol

1. Subjects: The subjects will be eight male rhesus monkeys (Macaca mulatta). The Contractor shall maintain each monkey on a diet of three to four monkey biscuits and one piece of fresh fruit per day in addition to fruit flavored pellets delivered during operant sessions (see below). Water will be freely available for all monkeys at all times. The Contractor shall house the monkeys in a humidity and temperature controlled room with a 12-hour light dark cycle (lights on from 7 a.m. to 7 p.m.).

Monkeys will be surgically implanted with double lumen Silicone rubber catheters (e.g., inside diameter

0.7 mm; outside diameter 2.0 mm diameter) to facilitate concurrent delivery of cocaine and treatment compounds. The Contractor shall implant catheters in the jugular or femoral vein, and the catheters will exit in the mid scapular region. All surgical procedures shall be performed under aseptic conditions.

Monkeys will initially be sedated with ketamine (5 mg/kg, s.c.), and anesthesia will be induced with sodium thiopental (10 mg/kg, i.v.). In addition, the Contractor shall treat the monkeys with 0.05 mg/kg atropine to reduce salivation. Following insertion of a tracheal tube, anesthesia will be maintained with halothane (1 1.5% in oxygen). After surgery, monkeys will be administered aspirin or acetaminophen (80 160 mg/day; p.o.) for 3 days. The antibiotic, Procaine Penicillin G (300,000 units/day, i.m.), will be administered every day for 5 days. The Contractor shall protect the i.v. catheter by a tether system consisting of a custom fitted nylon vest connected to a flexible stainless steel cable and fluid swivel.

This flexible tether system will permit monkeys to move freely. Catheter patency will be evaluated periodically by i.v. administration of a short acting barbiturate, methohexital (3 mg/kg i.v.), or ketamine (2 3 mg/kg i.v.).

The Contractor shall conduct animal maintenance and research in accordance with the guidelines provided by the NIH Committee on Laboratory Animal Resources. The facility must be licensed by the United States Department of Agriculture and protocols must be approved by the Institutional Animal Care and Use Committee. Consulting veterinarians periodically shall monitor the health of the

- 13 -monkeys. Monkeys will have visual, auditory, and olfactory contact with other monkeys throughout the study. Operant food and drug self administration procedures will provide an additional opportunity for environmental manipulation and enrichment.

2. Apparatus: The Contractor shall house each monkey individually in a well ventilated stainless steel chamber. The Contractor shall modify either the home cages or test environments of all monkeys to include an operant panel mounted on the front wall. The Contractor shall arrange three square translucent response keys in a horizontal row on the operant panel. Each key can be transilluminated by red, green, or white stimulus lights. In addition, three circular translucent panels will be located in a vertical column below the center response key and can be transilluminated by red, green, or white stimulus lights. The operant panel will also support an externally mounted pellet dispenser that delivers one gram of fruit flavored food pellets to a food receptacle mounted on the cage beneath the operant response panel. The Contractor shall mount two syringe pumps above each cage for delivery of saline or drug solutions through the intravenous catheters. The Contractor shall operate the operant panels and data collection with appropriate computers located in a separate room.

3. Self-administration - initial training procedures: Under this basic protocol, food and i.v. injections are available during three alternating components: (1) a 5 minute food component, (2) four 20 minute drug components separated by 5-minute timeouts, and (3) a second 5 min food component. Both food and i.v. injections are available under a FR30 schedule of reinforcement. During the 2 food components, the response key is transilluminated red, and the maximum number of pellets per component is 25.

During the drug component, the response key is transilluminated green, and the maximum number of injections is 25 per drug component. During these 20-minute components, different doses of cocaine or saline may be available. Following the delivery of each food pellet or drug injection, there is a 10-second timeout period, during which the stimulus light illuminating the center response key is turned off and responding has no scheduled consequences. In addition, the appropriate colored stimulus light (red for food, green for injections) is illuminated for one second below the center response key. The food and drug components are separated by 5 minute timeout periods when the response key is dark and responding has no scheduled consequences. The entire food/drug/food session lasts 120 minutes and will occur daily in the mid-afternoon (e.g., 3 5 p.m.).

In addition to the food/drug/food session described above, the Contractor shall give the monkeys the opportunity to self administer additional food pellets during supplementary food sessions running from 7 8 p.m. and 6 7 a.m. During these sessions, food will be available under a FR 30 / Timeout 10-second schedule, and monkeys can earn a maximum of 25 pellets per session. These additional food sessions provide additional enrichment opportunities for the monkeys and behavioral information that may reveal health problems.

During training, the Contractor shall alternate the solution available for self administration during the drug components between 0.032 mg/kg/inj cocaine (the maintenance dose of cocaine) and saline, with a non-contingent priming injection signaling the available dose.