FBO_Solicitation_for_NIHDA201800011_NIDA_Ref._Number_N01DA-18-8939.pdf

OMB #0990-0115

National Institute on Drug Abuse

Request for Proposal (RFP) No. NIHDA201800011 NIDA Reference Number: N01DA-18-8939

“Toxicological Evaluations of Potential Medications”

Issued by:

Lisa V. Bielen, Contracting Officer NIDA Section, Contracts Management Branch Blue Office of Acquisition, NIDA 6001 Executive Blvd, Room 4211 - MSC 9559 Bethesda, MD 20892-9559 Point of Contact: Lisa Bielen, Contracting Officer E-Mail: lisa.bielen@nih.gov Phone: 301.443.6677

DATE ISSUED: Tuesday, March 13, 2018 PROPOSAL DUE DATE: Monday, April 26, 2018, 3:00 P.M. Eastern Time

The National Institute on Drug Abuse invites you to submit a proposal responding to the requirements of this RFP No. NIHDA201800011 titled “Toxicological Evaluations of Potential Medications ".

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.

NIDA expects to award a single indefinite delivery indefinite quantity (task order) type contract with individually negotiated task orders over a five-year period of performance.

Cost reimbursement and/or firm fixed price task orders are expected to be awarded concurrently with and after contract award. All funding will be made through issuance of task orders and will be dependent on program needs and funding availability.

The contract will contain a minimum of $128,000 (minimum funded by task orders concurrent with award) and a maximum of $9,750,000 (maximum) for the entire contract period. It is anticipated that the initial performance period will start on or around August 23, 2018. Offerors should respond with technical and pricing proposals based on the assumptions provided in Section C and L. Offerors must include all of the tasks (1-19) listed in Task Requirements found in Article C.1 Statement of Work of the RFP in your technical proposal. Please include separate pricing for each of the four sample task orders A, B, C, and D (See Attachment 8).

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 lisa.bielen@nih.gov by Monday, March 26, 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, 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.

Requests for Information (RFIs)

Requests for clarification, additional information, or correction must be made in writing to the Contracting Officer. RFIs must be submitted on or before 3:00 p.m. on Monday, March 26, 2018.

RFIs may be submitted by e-mail to lisa.bielen@nih.gov with the subject line “RFI – RFP NIHDA201800011” or by letter to the Contracting Officer’s address above.

NOTICE: A permanent approval for class deviations to FAR 52.227-11, Patent Rights and FAR Clause 52.227-17, Rights in Data- Special Works was issued for use by NIDA when procuring contracts for confidential routine screening, pharmacokinetic, pharmaceutic and product development services for compounds under NIDA’s Medication Development Program. NIDA intends to include these clause deviations in any resulting contract from this solicitation, subject to approval of a determination of exceptional circumstances by the Director, NIH. The deviation clauses are set forth in ARTICLE I.4 of this solicitation. Please review and provide any comments on these deviated clauses in the offeror's questions due Monday, March 26, 2018.

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 11.

A completed Form NIH-2043, “Proposal Summary and Data Record” (Attachment 9) 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.

mailto:lisa.bielen@nih.gov mailto:lisa.bielen@nih.gov http://rcb.cancer.gov/rcb-internet/forms/2043.pdf http://ocm.od.nih.gov/contracts/rfps/TechCov.htm

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 Thursday, April 26, 2018 at 3:00 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 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 Lisa Bielen, 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, Contract’s Management Branch Blue should not occur.

Sincerely, Lisa V. Bielen, Contracting Officer NIDA Section, Contracts Management Branch Blue Office of Acquisitions, NIDA/NIH

Enclosure https://ecps.nih.gov/ 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: Public Law 102-321 as amended

2. Request for Proposal (RFP) Number:

NIHDA201800011

3. Issue Date:

03/13/2018

4. Set Aside:

[X] No

[ ] Yes See Part IV Section L

5. Title : Toxicological Evaluations of Potential Medications

6. ISSUED BY:

NIDA Section Contracts Management Branch Blue Office of Acquisition, NIDA National Institutes of Health 6001 Executive Blvd., Room 4211 (MSC 9559) Bethesda, MD 20892-9559 * *If using a delivery service, change the city and zipcode to Rockville, MD 20852

7. SUBMIT OFFERS TO:

See Part III, Section J, "Packaging and Delivery of Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website," 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 Attachment 1, "Packaging and Delivery of Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website," until 3:00 pm local time on April 26, 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 Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website." The OFFICIAL POINT OF RECEIPT for determining TIMELY DELIVERY is the eCPS Website.

IF YOUR PROPOSAL IS NOT RECEIVED BY THE eCPS WEBSITE AT THE TIME SPECIFIED, 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: Lisa Bielen, Contracting Officer

PHONE: (301) 443-6677

e-MAIL: lisa.bielen@nih.gov

COLLECT CALLS WILL NOT BE ACCEPTED.

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

RFP Number : NIHDA201800011

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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. TASK ORDERS UNDER SINGLE AWARD INDEFINITE DELIVERY CONTRACTS

e. BRAND NAME OR EQUAL

f. COMMITMENT OF PUBLIC FUNDS

g. PROMOTING EFFICIENT SPENDING

h. COMMUNICATIONS PRIOR TO CONTRACT AWARD

i. RELEASE OF INFORMATION

j. CONCEPT REVIEW

k. PREPARATION COSTS

l. SERVICE OF PROTEST

m. LATE PROPOSALS AND REVISIONS

n. AVAILABILITY OF THE "FEDERAL ADP AND TELECOMMUNICATIONS STANDARDS INDEX."

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

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7. Potential Award Without Discussions

8. Use of the Metric System of Measurement

9. Standards for Privacy of Individually Identifiable Health Information

10. Non-discrimination for Conscience, HHSAR Clause 352.270-9

11. Privacy Act - Treatment of Proposal Information

12. Selection of Offerors

13. Institutional Responsibility Regarding Investigator Conflicts of Interest

14. ROTC Access and Federal Military Recruiting on Campus

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. Cost and Pricing Data

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

6. Salary Rate Limitation

7. Small Business Subcontracting Plan

8. Mentor Protege Program, HHSAR 352.219-70

9. HUBZone Small Business Concerns

10. Total Compensation Plan

11. Other Administrative Data

12. Qualifications of the Offeror

13. Subcontractors

14. Proposer's Annual Financial Report

15. 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 DATA SHARING PLAN

6. TECHNICAL EVALUATION FACTORS

7. EVALUATION OF ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY- SECTION

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 REQUIRED) 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

This research and development contract will support pre-clinical acute and repeat dose toxicology and safety pharmacology studies in rodents, rabbits, dogs, and/or monkeys, which support the development of potential pharmacotherapies (medications) to treat substance use disorders. This contract also will support drug interaction studies in rodents, rabbits, dogs, and/or monkeys to assess the safety of potential medications when administered alone and in combination with abused substances.

ARTICLE B.2. PRICES/COSTS

a. This is an Indefinite Quantity contract as contemplated by FAR 16.504. The Contractor shall be reimbursed by the Government in an amount not less than a total of $128,000 (minimum) nor more than a total of $9,750,000 (maximum) for successful performance of this contract.

b. For cost reimbursement task orders, the fixed fee for individual task orders will be negotiated by task order. The fixed fee shall be paid in installments as negotiated (based on percentage of completion of work or the percent of total effort expended), as determined by the Contracting Officer, and 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. Payment of fixed fee shall not be made in less than monthly increments.

c. The costs/prices set forth in this ARTICLE will cover the contract period August 2018 through August 2023.

d. The Government will issue cost reimbursement and/or fixed price Task Orders based on the work described in SECTION C of this contract.

e. Ordering procedures are described in the TASK ORDER PROCEDURE Article in SECTION G 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)

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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.

[Remainder of the page left intentionally blank]

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SECTION C - DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

ARTICLE C.1. STATEMENT OF WORK

I. Introduction/Background

A. Background Information

The NIDA Medications Discovery and Toxicology Branch has the mission to facilitate, through preclinical medications discovery and safety assessment efforts, the translation of basic research findings into pharmacotherapies for the treatment of substance use disorders. When preclinical development candidates are identified, this contract provides a resource for the development of safety data that support filing Investigational New Drug (IND) applications and New Drug Application(s) (NDA) to the U.S. Food and Drug Administration (FDA). In this context, the primary objective of this research and development contract is to support preclinical acute and repeat dose toxicology and safety pharmacology studies in rodents, dogs and/or monkeys on test articles that are potential pharmacotherapies (medications) to treat substance use disorders. It is anticipated that NIDA will use the results of these preclinical studies in IND and NDA filings with the FDA in accordance with FDA regulations, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and Good Laboratory Practice for Nonclinical Laboratory Studies (GLP) regulations. NIDA reserves the right to have the contracted services benefit NIDA and any other component of the National Institutes of Health (NIH).

II. References

US Food and Drug Administration Pharm/Tox Guidances ( http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm)

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Safety Guidelines ( http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html)

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Multidisciplinary Guidelines ( http://www.ich.org/products/guidelines/multidisciplinary/article/multidisciplinary-guidelines.html)

Good Laboratory Practice for Nonclinical Laboratory Studies; 21 CFR, Chapter 1, Subchapter A, Part 58 ( http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58)

Health Effects Testing Guidelines; 40 CFR Chapter 1, Subpart C (Oral Toxicity), § 798.2650

Health Effects Testing Guidelines; 40 CFR Chapter 1, Subpart E (Specific Organ/Tissue Toxicity), § 798.4700

Health Effects Testing Guidelines; 40 CFR Chapter 1, Subpart G (Neurotoxicity), § 798.6050

III. Scope and Tasks

A. General Requirements

1. Independently, and not as an agent of the Government, the Contractor shall furnish the necessary services, qualified personnel, materials, equipment and facilities, not otherwise furnished by the Government under the terms of the contract. Unless otherwise directed by the NIDA Contracting Officer Representative (COR) the Contractor shall use established techniques and study parameters as well as statistical methods of data analysis in accord with current FDA GLP regulations. The Contractor shall submit data/reports to NIDA, which in turn may submit the data to the FDA as part of an IND or NDA. Thus, NIDA requires that the report format shall conform to the highest scientific standards.

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html http://www.ich.org/products/guidelines/multidisciplinary/article/multidisciplinary-guidelines.html http://www.ich.org/products/guidelines/multidisciplinary/article/multidisciplinary-guidelines.html http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58

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The Contractor shall use appropriate statistical methods to analyze the study data. As part of each study protocol, the Contractor shall clearly describe the methods, including data transformation methods and rationale. NIDA shall not accept reference to statistical software programs that do not reveal the exact procedures/steps in the statistical analyses.

2. All work under this contract shall be monitored by the COR, whose position is defined in Section G of this contract.

3. Unless specified otherwise by the COR, the Contractor shall conduct all studies in accordance with the GLP Regulations. Unless directed otherwise by the COR, the Contractor shall use strains and species for the in vivo studies as follows: mouse (CD-1 or similar), rat (Sprague-Dawley or Long Evans), rabbit (New Zealand white), dog (purpose-bred beagle), guinea pig (Hartley) and monkey (Macaca fascicularis (crab-eating macaque) also known as cynomolgus monkey).

Unless otherwise directed by the COR, the Contractor shall conduct analytical assays to determine the homogeneity, stability and the actual concentration of the test article in dosing solutions or suspensions and the Contractor shall determine the concentration of the test article in the dosing solutions or suspensions as specified for each study protocol. In addition, the Contractor shall verify the identity of the test article when it is received.

The Contractor shall assume, for the purposes of developing a budget, that a gas chromatography (GC) or high performance liquid chromatography (HPLC) assay without derivatization shall be the basis for the analytical method.

During contract performance, NIDA shall furnish a suggested assay procedure for validation in the Contractor's laboratory for each study. The Contractor shall assume for the purposes of preparing a budget that a spectral assay procedure such as mass spectroscopy or nuclear magnetic resonance (NMR) shall be used to verify the identity of the test article.

B. Specific Requirements and Schedule of Work

As necessary, NIDA will issue Task Orders for the Contractor to perform any or all of the tasks listed below. NIDA will not necessarily issue Task Orders for each of the tasks below to be performed during each year of the contract. NIDA may issue each of the Task Orders one or more times. NIDA may decide not to issue Task Orders for one or more of the tasks listed below. The amount of work will depend upon the needs of NIDA's program office and the availability of funds. The amount of work may vary from year to year. Due to changes in priorities within NIDA, the projected workload cannot be precisely described for each year.

After NIDA issues and awards a Task Order, the Contractor will carry out the Task Order. The Contractor shall perform the tasks if and as directed in awarded task orders. Specific details for each Task Order must be approved by the NIDA Contracting Officer and COR prior to initiation of each project. Unless otherwise requested by NIDA, the Contractor will send all materials to the COR electronically using NIDA's secure server (e.g., Livelink).

1. Task Requirements

Specifically, the Contractor shall perform the following tasks.

Task 1: The Contractor shall conduct acute drug interaction safety studies in rodents. Specific methods to be used in these studies shall be subject to the approval of the COR. The objective of these studies shall be to determine the safety of the test article in combination with cocaine, methamphetamine, an opiate, or ethanol.

Typically, the Contractor shall use at least 10 rats (all male or 5 male and 5 female) per treatment group and a total of 12 treatment groups per study. In studies with cocaine or methamphetamine, effects on lethality and on convulsions shall be assessed. In studies with an opiate, effects on lethality shall be assessed; the response to a thermal stimulus may be assessed also. In studies with ethanol, effects on lethality shall be assessed; the effects on performance on a rotating rod may be assessed also. All test article and interaction article dosing solutions shall be assayed to verify identity and concentration. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 2: The Contractor shall conduct cardiovascular interaction safety studies in conscious, unrestrained telemetered dogs or monkeys. Specific methods to be used in the study shall be subject to the approval of the COR.

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The objective of this study shall be to evaluate the cardiovascular effects that may result following oral (gavage) administration a test article and intravenous administration of cocaine (interaction article) or methamphetamine (interaction article) in unrestrained dogs or monkeys.

Typically, the Contractor shall use at least six male dogs or four monkeys per group for the vehicle control and test article treatment groups. The animals shall be instrumented with surgically implanted transducers that can continuously monitor and report report body temperature, hemodynamic parameters (to include systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate) and electrocardiograms (to include PR, QRS, RR, QT and QTc intervals) and be implanted with a titanium vascular access port. The instrumented test animals shall be allowed to fully recover (typically 4 to 6 weeks) before the dosing phase of the study commences.

The aforementioned measurements shall be recorded using a remote telemetry system. There would be a total of nine treatments. There shall be vehicle control groups for both the test article and cocaine and the dose levels of test article and cocaine to be tested shall be specified by the COR. At least two dose levels of the test article shall be administered in combination with cocaine vehicle and again in the presence of at least two dose levels of cocaine.

The interaction article, cocaine or its vehicle shall be administered intravenously using a programmable infusion pump carried in a jacket or back pack worn by the animal via a surgically implanted vascular access port. Typically, each treatment combination shall be separated by at least 5 days. There shall be no personnel in the animal room after the vehicle control or test article has been administered. Infusion pumps shall have the capacity to record, store and report the actual time, duration and volume of the interaction article dose and those data shall be included in the study report.

A veterinary cardiologist shall evaluate the electrocardiography recording. The findings shall be presented in a comprehensive report that shall include tabulations and graphical representations of the collected individual and averaged data. Comparisons shall be made between the experimental results of the test and interaction articles alone, and the test article in the presence of cocaine or methamphetamine. Appropriate statistical methods shall be used to determine treatment-related effects for all the data that are collected. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 3: The Contractor shall utilize ex vivo tissue preparations to determine the effects of potential medications on cardiac conductance. Unless otherwise instructed by the COR, the Contractor shall conduct a manual patch clamp hERG assay for assessment of drug interactions with the hERG potassium channel responsible for IKr, the rapid delayed rectifier current that mediates cardiac action potential repolarization and an action potential duration assay in Purkinje fibers isolated from sheep, rabbit or dog to determine effects on cardiac action potentials. Specific methods to be used in the study shall be subject to the approval of the COR. The findings shall be presented in a comprehensive report that shall include tabulations and graphical presentations of the collected individual and averaged data.

Appropriate statistical methods shall be used to determine treatment-related effects for all the data that is collected.

NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 4: The Contractor shall conduct mutagenicity studies with a battery of up to five tests which may include:

(1) Salmonella & E. coli Plate Incorporation Assay with an Independent Confirmatory Repeat of the Plate Incorporation Assay,

(2) L51178Y/TK+/- Mouse Lymphoma Gene and Chromosomal Mutation Assay with an Independent Confirmation Repeat of the Mutagenesis Assay,

(3) Chromosomal Analysis Using Chinese Hamster Ovary Cells with an Independent Confirmatory Repeat of the Cytogenetic Assay

(4) Chromosomal Analysis Using Human Lymphocytes with an Independent Confirmatory Repeat of the Cytogenetic Assay, and

(5) In vitro Micronucleus Assay with an Independent Confirmatory Repeat that Includes 2 Harvest Times.

NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 5: The Contractor shall conduct acute dosing toxicity studies in the rat and/or mouse by the intravenous and oral (gavage) routes of administration. Typically, the Contractor shall conduct range-finding studies with three animals of each sex per treatment group. NIDA may require a minimum of four groups including a vehicle-treated control and a maximum of six treatment groups for each study. Evaluations shall include recording of clinical signs, especially

- 9 -stereotypic behavior, at approximately 6 intervals on the day of dosing and once daily thereafter. The Contractor shall weigh the animals daily during the first week following treatment and at termination. Under these range-finding studies, the Contractor shall perform a necropsy, but shall not save any tissues. Definitive acute studies performed by the intravenous and oral (gavage) routes of administration shall follow the range finding studies. The Contractor shall use four or five treatment groups evenly divided by sex. NIDA requires at least eight animals of each sex per group. The Contractor shall perform the same evaluations conducted in the range finding study. Under these definitive studies, at necropsy, the Contractor shall typically collect and preserve approximately 42 tissues per animal.

In addition, in an intravenous median lethal dose (LD50) study (only) the Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing from extra "satellite" animals for the determination of plasma levels of the test article. NIDA requires three animals of each sex per treatment group for each determination point. The Contractor shall ship these samples to another laboratory for analysis (Another NIH contract shall pay the cost of this analysis).

The Contractor shall conduct statistical comparisons between test article-treated and control animals to determine the maximum tolerated dose level (MTD) and the no-observable-effect level (NOEL). If possible, the Contractor shall calculate an LD50. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 6: The Contractor shall conduct repeat dosing toxicity studies in dogs and/or monkeys. Typically, each study shall be divided into 2 Phases and shall require 10 animals. Phase I shall include two groups of four animals, a vehicle control group (Group 1) and a test article group (Group 2), each evenly divided by sex. The Contractor shall administer the initial test article dose level for 4 days and then repeatedly increase the level for 4-day intervals until determining the MTD. NIDA estimates that there shall be 16 days of daily dosing in this phase of the study (4 days at 4 levels each). The Contractor shall return animals (Group 2) treated with the test article in the first phase to the NIDA stock colony (at the Contractor's site) after a recovery period.

Phase II shall consist of two groups, also. The vehicle control group shall include one male and one female. The test article treatment group shall consist of the two animals of each sex that also served as Group 1 in Phase I. The second phase of the MTD study shall cover 14 days. The Contractor shall treat the animals that received only vehicle in the first phase with the test article at a fixed dose level daily for 14 consecutive days. The Contractor shall typically collect blood samples on Study Days (SD) 1 and 14 at 6 intervals on each of these days for determination of the parent test article plasma concentration. A separate laboratory, under a separate NIH contract, shall perform the determination of plasma test article levels. The Contractor shall perform necropsy and save tissues from all animals in the second phase. Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund. Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

Task 7: The Contractor shall conduct 14-day repeat dose range-finding toxicity studies in rats by the oral (gavage) route of administration. Typically, each study shall require at least 30 rats of each sex for each test article studied. In-life evaluations shall include (1) body weights (determined daily during the first week, once weekly thereafter and at termination), and (2) detailed physical signs 3 times daily for the first week, once daily thereafter and at termination.

The Contractor shall perform clinical pathology evaluations on all surviving rats at termination. Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund. Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

The Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing on the first and last days of dosing from extra "satellite" animals for the determination of plasma levels of the test article. Typically, each satellite group shall contain three animals of each sex for each determination point. The Contractor shall ship these samples a NIDA-designated laboratory for analysis. Another NIH contract shall cover the cost of this analysis.

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In addition, the Contractor shall as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between vehicle control- and test article-treated animals to determine the MTD and NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 8: The Contractor shall conduct 28-day repeat dose toxicity studies in rats by the oral (gavage) route of administration. Typically, each study shall require at least 120 rats (60 of each sex) for each test article studied.

The Contractor shall assign 10 of each sex to each of 4 groups (one vehicle control- and three test article-treated groups). The Contractor shall sacrifice these animals at the end of the dosing period for pathology studies. In addition, the Contractor shall assign an additional 10 animals of each sex to the vehicle control and highest dose test article groups. These animals shall remain on study after 28 days of dosing and be allowed to recover for 14 days. During the recovery period, no additional dosing shall occur, but all in-life observations conducted during the treatment phase shall continue. In-life evaluations shall include (1) body weights (determined daily during the first week, twice weekly thereafter and at termination), (2) detailed physical signs 3 times daily for the first week, 3 times weekly thereafter and at termination. The Contractor shall examine all animals on test at these intervals. The Contractor shall perform clinical pathology evaluations on all surviving animals at termination. Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund.

Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

The Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing on the first and last days of dosing from extra "satellite" animals for the determination of plasma levels of the test article. Typically, each group shall consist of three animals of each sex for each determination time point. The Contractor shall ship these samples to a NIDA-designated laboratory for analysis. Another NIH contract shall cover the cost of this analysis.

In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between treated and control animals to determine the MTD level, treatment-related effects and the NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 9: The Contractor shall conduct 28-day repeat dose toxicity studies in dogs or monkeys by the oral (gavage) route of administration. Typically, the Contractor shall use at least 64 dogs or monkeys (32 of each sex) for each test article studied. The Contractor shall assign three of each sex to each of four treatment groups (1 vehicle control and 3 test article groups). The Contractor shall sacrifice these animals at the end of the dosing period for pathology studies. The Contractor shall assign two additional animals of each sex to the control and highest dose test article treatment groups. These animals shall remain on study after 28 days of dosing and recover for 14 days. During the recovery period, no additional dosing shall occur, but all in-life observations conducted during the treatment phase shall continue. In-life evaluations shall include (1) body weights (determined daily during the first week, 3 times weekly thereafter and at termination), (2) detailed physical signs daily throughout the study. The dogs or monkeys shall receive two pretest evaluations for clinical pathology (including electrocardiography and ophthalmology) and interim evaluations at 7 and 14 days. The Contractor shall examine all animals on study at these intervals. Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund. Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

The Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing on the first and last days of dosing from all animals for the determination of plasma levels of the test article. The Contractor shall ship these samples to another laboratory for analysis. Another NIH contract shall cover the cost of this analysis.

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In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between treated and control animals to determine the MTD level, treatment related effects and the NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 10: The Contractor shall conduct 90-day repeat dose toxicity studies in rats by the oral (gavage) route of administration. Typically, each study shall require at least 160 rats (80 of each sex) for each test article studied.

The Contractor shall assign 15 rats of each sex to each of 4 treatment groups (1 vehicle control group and 3 test article groups). The Contractor shall sacrifice these animals at the end of the dosing period for pathology studies.

The Contractor shall also assign 10 additional animals of each sex to the vehicle control and highest dose test article groups. These animals shall remain on study after 90 days of dosing and recover for 30 days. During the recovery period, no additional dosing shall occur, but all in-life observations conducted during the treatment phase shall continue. In-life evaluations shall include: (1) body weights (determined daily during the first week, once weekly thereafter and at termination) and (2) detailed physical signs 3 times daily for the first week, once daily thereafter and at termination. The Contractor shall perform clinical pathology evaluations on all surviving animals at termination.

Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund. Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

The Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing on the first and last days of dosing from extra "satellite" animals for the determination of plasma levels of the test article. Typically, each group shall contain three per sex for each determination point. The Contractor shall ship these samples to another laboratory for analysis. Another NIH contract shall cover the cost of this analysis.

In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between vehicle control and test article-treated animals to determine the MTD level, treatment-related effects and the NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 11: The Contractor shall conduct 90-day repeat dose toxicity studies in dogs or monkeys, as specified by the COR, by the oral (gavage) route of administration. Typically, the Contractor shall utilize 40 animals (20 of each sex). The Contractor shall assign four animals of each sex to each of four treatment groups (one vehicle control and three test article groups). The Contractor shall sacrifice these animals at the end of the dosing period for pathology studies. In addition, the Contractor shall also assign two additional animals of each sex to the vehicle control and highest test article dose groups. These animals shall remain on study after 90 days of dosing and recover for 30 days. During the recovery period, no additional dosing shall occur, but all in-life observations conducted during the treatment phase shall continue. In-life evaluations shall include: (1) body weights (determined daily during the first week, twice weekly thereafter and at termination) and (2) detailed physical signs daily for the first week, three times weekly thereafter and at termination. The dogs or monkeys shall receive two pretest evaluations for clinical pathology (including electrocardiography and ophthalmology) and interim evaluations at 30 and 60 days. The Contractor shall examine all animals on study at these intervals. The Contractor shall perform clinical pathology evaluations on all surviving animals at termination. Evaluations shall include complete hematology and clinical chemistry evaluations, as specified in the harmonization guidelines in Weingand et al., Fund. Appl. Toxicol. 29:198-201, 1996. The Contractor shall perform histopathology of all major tissues and gross lesions (approximately 42 tissues per animal) in the test article-treated and the control group animals as set forth in 40 CFR, Chapter 1, Subpart C, § 798.2650. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

The Contractor shall typically collect plasma at 1, 2, 4, 8, 12 and 24 hours post dosing on the first and last days of dosing from all animals for the determination of plasma levels of the test article. The Contractor shall ship these samples to another laboratory for analysis. Another NIH contract shall cover the cost of this analysis.

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In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between treated and control animals to determine the MTD level, treatment-related effects and the NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 12: The Contractor shall conduct oral (gavage) studies of test article effects on the fertility and early embryonic development to implantation in rats as specified by the COR. The Contractor shall conduct the study design in accordance with ICH Harmonised Tripartite Guideline Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2) Section 4.1.1 and 40 CFR, Chapter 1, Subpart C, § 798.4700. Briefly, the Contractor shall assign 120 rats of each sex evenly to 4 groups. The Contractor shall treat the males 28 days prior to mating and the females 14 days prior to mating. Treatment for both sexes shall continue for the 2 weeks of mating. The Contractor shall treat the males for 2 weeks post-mating and the females for the first week of gestation. The Contractor shall conduct typical in-life evaluations, such as determination of body weight, food consumption, water consumption and physical signs at appropriate intervals. The Contractor shall also conduct uterine and sperm evaluations at termination (gestation day 13 for females and 13 days after the mating period for males).

In addition, the Contractor shall, as part of this Task, perform analytical services as specified above in Section II. A. 3.

of this Statement of Work.

The Contractor shall conduct statistical comparisons between treated and control animals to determine the MTD level, treatment-related effects and the NOEL. NIDA requires a complete report for each study and the requirements for report content and format shall conform to GLP guidelines.

Task 13: The Contractor shall conduct studies of a test article's effects on the prenatal development toxicity (also known as Segment II teratology) studies, both with range-finding and definitive components, in rats and rabbits.

The Contractor shall conduct the study design in accordance with ICH Harmonised Tripartite Guideline Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2) Section 4.1.2 and 40 CFR, Chapter…